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776 Cards in this Set
- Front
- Back
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what is the classical definition of immunity?
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defense against infectious pathogens
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what is innate immunity?
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aka natural immunity or native immunity
defense mechanisms that are present even before infection that have evolved to specifically recognize microbes and protect individuals against infections |
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what is adaptive immunity?
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aka acquired immunity or specific immunity
mechanisms that are stimulated by microbes and are capable of recognizing microbial and nonmicrobial substances |
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by convention, to what does the term "immune response" refer?
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adaptive immunity
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what are the major components of the innate immunity?
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epithelial barriers
phagocytic cells dendritic cells natural killer (NK) cells complement proteins |
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what are the two most important cellular reactions of innate immunity?
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inflammation
anti-viral defense |
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why is inflammation important to innate immunity?
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recruits and activates phagocytic leukocytes to kill microbes
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what cells mediate anti-viral defense of innate immunity?
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dendritic cells
NK cells |
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what are pathogen-associated molecular patterns?
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components of microbes that are shared among related microbes and are often essential for the infectivity of these pathogens
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why can pathogen associated molecular patterns (PAMPs) not be mutated to allow the microbes to evade defense mechanisms?
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they are often essential for the infectivity of the pathogens that contain them
(mutations would hinder the infectivity of the pathogens) |
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what are danger-associated molecular patterns?
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molecules released by injured and necrotic cells
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what are the cellular receptors that recognize pathogen- and danger-associated molecular patterns?
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pattern recognition receptors
ex. toll-like receptors (TLRs) |
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how do TLRs signal upon recognition of microbes?
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TLRs and other sensors signal by a common pathway that leads to the activation of transcription factors, notably NF-kappaB
NF-kappaB turns on the production of cytokines and proteins that stimulate the microbicidal activities of phagocytes |
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what are the mechanical barriers to the entry of microbes from the external environment?
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epithelia of the skin, GI tract, and respiratory tract
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what anti-microbial molecules are produced by epithelia?
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defensins
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what phagocytes in the blood can rapidly be recruited to any site of infection?
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monocytes
neutrophils |
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what is the name for monocytes that enter the tissues and mature?
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macrophages
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how do dendritic cells inhibit viral infection and replication?
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produce type I interferons (anti-viral cytokines)
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how can complement function as a part of both the innate and adaptive immune systems?
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in innate immunity, complement system is activated by microbes using the alternative and lectin pathways
in adaptive immunity, complement system is activated by antibodies using the classical pathway |
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what circulating proteins are part of innate immunity?
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complement proteins
mannose-binding lectin C-reactive protein |
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how is lung surfactant considered a part of innate immunity?
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it provides protection against inhaled microbes
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what are the components of the adaptive immune system?
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lymphocytes and their products (antibodies)
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what are the two subtypes of adaptive immunity?
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humoral
cell-mediated (cellular) |
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what is humoral immunity responsible for?
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protection against extracellular microbes and their toxins
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what is cell-mediated immunity responsible for?
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protection against intracellular microbes
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what cells mediate humoral immunity?
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B (bone marrow-derived) lymphocytes
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what cells mediate cell-mediated immunity?
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T (thymus-derived) lymphocytes
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what is another name for antibodies?
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immunoglobulins
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where do lymphocytes reside?
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not fixed in particular tissues, but are capable of migrating among lymphoid and other tissues and the vascular and lymphatic circulations
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what are naive lymphocytes?
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mature lymphocytes that have not been exposed to the antigen for which they are specific
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into what two types of cells do activated lymphocytes differentiate?
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effector cells - perform function of eliminating microbes
memory cells - live in a state of heightened awareness and are better able to combat the microbe in case it returns |
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what percent of circulating lymphocytes are T lymphocytes?
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60% to 70%
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where can mature T lymphocytes be found?
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in the blood
in T-cell zones of peripheral lymphoid organs |
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what is the function of the alpha-beta T-cell receptor?
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recognize peptide antigens that are displayed by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells (APCs)
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what is MHC restriction?
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limitation of the specificity of T cells for peptides displayed by cell surface MHC molecules
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what is the effect of MHC restriction?
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ensures that T cells see only cell-associated antigens (e.g. those derived from microbes in cells)
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how is T-cell receptor diversity generated?
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somatic rearrangement of the genes that encode the T-cell receptor alpha and beta chains
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the enzyme in developing lymphocytes that mediates rearrangement of antigen receptor genes is the product of what genes?
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RAG-1
RAG-2 (RAG = recombination activating gene) |
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what is the result of inherited defects in RAG proteins?
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RAG = recombination activating genes
defects result in a failure to generate mature lymphocytes |
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how many different TCR molecules are expressed on T cells?
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each T cell expresses only a single TCR specificity
the full complement of T cells in an individual is capable of recognizing a very large number of antigens |
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what cells contain germline TCR genes?
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all non-T cells in the body contain germline (unrearranged) TCR genes
ONLY T cells contain rearranged TCR genes |
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what is the diagnostic advantage to each T cell and its progeny having a unique DNA rearrangement (unique TCR)?
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it is possible to distinguish polyclonal (non-neoplastic) T-cell proliferations from monoclonal (neoplastic) T-cell proliferations
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to what is each TCR noncovalently linked?
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five polypeptide chains which form the CD3 complex and the zeta chain dimer
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what is the function of the CD3 and zeta proteins?
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involved in the transduction of signals into the T cell
they are invariant (identical) in all T cells |
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what is recognized by the gamma-delta T-cell receptor?
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peptides
lipids small molecules no requirement for display by MHC proteins |
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where do gamma-delta T-cells tend to aggregate?
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epithelial surfaces, such as the skin and mucosa of the GI and urogenital tracts
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what is recognized by NK-T cells?
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glycolipids that are displayed by CD1 (MHC-like molecule)
very limited diversity of TCRs |
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what type of MHC molecules are bound by CD4 molecules?
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CD4 molecules in CD4+ T cells bind to class II MHC molecules that are displaying antigen
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what type of MHC molecules are bound by CD8 molecules?
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CD8 molecules in CD8+ T cells bind to class I MHC molecules that are displaying antigen
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what molecules are bound by CD28?
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CD80 (B7-1) or CD86 (B7-2)
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what is CD28?
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one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation; CD28 is the receptor for CD80 and CD86
Stimulation through CD28 in addition to the TCR can provide a potent co-stimulatory signal to T cells for the production of various interleukins (IL-2 and IL-6 in particular) association of the T cell receptor of a naive T cell with MHC:antigen complex without CD28:B7 interaction results in a T cell that is anergic. |
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what is CD80?
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aka B7-1
a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival it is the ligand for two different proteins on the T cell surface: CD28 (for autoregulation and intercellular association) and CTLA-4 (for attenuation of regulation and cellular disassociation) |
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what is CD86?
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aka B7-2
a protein expressed on antigen-presenting cells that provides costimulatory signals necessary for T cell activation and survival it is the ligand for two different proteins on the T cell surface: CD28 (for autoregulation and intercellular association) and CTLA-4 (for attenuation of regulation and cellular disassociation) |
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what are the two membrane-bound antibodies?
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IgM
IgD present on the surface of all mature, naive B cells |
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what are the antigen binding components of the B-cell receptor complex?
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membrane-bound antibodies (IgM and IgD)
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from what is the unique antigen specificity of B cell receptors derived?
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RAG-mediated rearrangements of Ig genes
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what is a useful method of identifying monoclonal B-cell tumors?
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analysis of Ig gene rearrangements
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a heterodimer of what two invariant proteins are contained in the B-cell antigen receptor? what is their function?
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Igalpha
Igbeta essential for signal transduction through the antigen receptor |
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what receptor is bound by the Epstein-Barr virus (EBV)?
what cells does it infect? |
EBV binds the type 2 complement receptor (CR2/CD21)
CR2 is present on B cells and so are readily infected by EBV |
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what are the two cells with dendritic morphology?
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interdigitating dendritic cells (dendritic cells)
follicular dendritic cells |
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what cells with dendritic morphology are known as just dendritic cells?
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interdigitating dendritic cells
the cells located in the epithelia and interstitia of all tissues |
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what are the most important antigen presenting cells (APCs) for initiating primary T-cell responses against protein antigens?
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interdigitating dendritic cells (dendritic cells)
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where are interdigitating dendritic cells (dendritic cells) located?
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under epithelia (common site of entry of microbes and foreign antigens)
interstitia of all tissues (where antigens may be produced) |
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what are Langerhans cells?
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immature interdigitating dendritic cells (dendritic cells) within the epidermis
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what features account for the key role of interdigitating dendritic cells (dendritic cells) in antigen presentation?
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1) location
2) expression of many receptors for capturing/responding to microbes/antigens (TLRs & mannose receptors) 3) recruited to T-cell zones of lymphoid organs in response to microbes (to present to T cells) 4) express high levels of costimulatory molecules for T cells |
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what is the response of dendritic cells to microbes?
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after binding the microbes via TLRs or mannose receptors, etc., the dendritic cells travel to the T-cell zones of lymphoid organs, where they are ideally located to present antigens to T cells
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where are follicular dendritic cells located?
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germinal centers of lymphoid follicles in the spleen and lymph nodes
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what receptors are present on follicular dendritic cells?
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Fc receptors for IgG
receptors for C3b (CR1) |
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what kinds of antigens can be bound by follicular dendritic cells?
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antigen bound to antibodies or complement proteins
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what is the role of follicular dendritic cells?
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present antigens to B cells and select the B cells that have the highest affinity for the antigen
initiate humoral response |
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what is the function of macrophages in T cell activation?
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function as antigen presenting cells
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what is the effect of T cells on macrophages?
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T cells activate macrophages and enhance their ability to kill ingested microbes
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what percentage of circulating lymphocytes is made up of natural killer cells?
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10-15%
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how do natural killer cells compare to other lymphocytes morphologically?
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somewhat larger
contain abundant azurophilic granules |
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what type of cells are known as "large granular lymphocytes"?
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natural killer cells
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are TCRs or BCRs (Igs) expressed on natural killer cells?
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neither TCRs nor BCRs are expressed on natural killer cells
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what two cell surface molecules are commonly used to identify NK cells?
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CD16
CD56 |
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what is CD16?
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an Fc receptor for IgG
confers on NK cells the ability to lyse IgG-coated target cells |
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what is ADCC?
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antibody-dependent cell-mediated cytotoxicity
ability of NK cells to lyse IgG-coated target cells, mediated by CD16 (Fc receptor for IgG) |
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how is the functional activity of NK cells regulated?
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a balance between signals from activating and inhibitory receptors
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what is the NKG2D receptor?
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activating receptor on NK cells that recognize surface molecules that are induced by various kinds of stress, such as infection and DNA damage
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what are the two major families of inhibitory receptors on NK cells?
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killer cell Ig-like receptors
CD94 family of lectins |
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what is recognized by NK cell inhibitory receptors?
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self-class I MHC molecules
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what is the purpose of NK cell inhibitory receptors?
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prevent NK cells from killing normal/healthy cells
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how is the balance tilted toward activation of NK cells in the case of virus infection or neoplastic formation?
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viral infection and neoplastic transformation often induce the expression of ligands for NK activating receptors and at the same time reduce the expression of class I MHC molecules
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what cytokines are secreted by NK cells?
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interferon-gamma (IFN-gamma)
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what cytokines regulate the activity of NK cells?
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IL-2 (stimulates proliferation)
IL-15 (stimulates proliferation) IL-12 (activates killing and secretion of IFN-gamma) |
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what are the principal generative lymphoid organs?
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thymus (where T cells develop)
bone marrow (where B cells develop) |
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what are the peripheral lymphoid organs?
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lymph nodes
spleen mucosal lymphoid tissues cutaneous lymphoid tissues |
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how are blood-borne antigens trapped in the spleen?
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trapped by dendritic cells and macrophages
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what are the two anatomically defined mucosal lymphoid tissues?
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pharyngeal tonsils
Peyer's patches of the intestine |
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where are B cells concentrated in lymph nodes?
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follicles
discrete structures located around the periphery or cortex of each node |
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what is a germinal center?
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central region of a follicle if the B cells in that follicle have recently responded to an antigen
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where are T cells concentrated in lymph nodes?
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in the paracortex, adjacent to the follicles
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where are the different dendritic cells located in lymph nodes?
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follicular dendritic cells - contained within B cell follicles (involved in the activation of B cells)
interdigitating dendritic cells - contained in the paracortex (present antigens to T cells) |
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where are T cells concentrated in the spleen?
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in periarteriolar lymphoid sheaths surrounding small arterioles
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where are B cells concentrated in the spleen?
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in follicles
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what happens when lymphocytes are activated by antigens?
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they alter their expression of chemokine receptors, leave their homes, migrate toward each other and meet at the edge of follicles, where helper T cells interact with and help B cells to differentiate into plasma cells
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how does migration differ between B cells and T cells?
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effector T cells have to locate and eliminate microbes at any site of infection
plasma cells (effector B cells) remain in the lymphoid organs and secrete antibodies that are carried to distant tissues |
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what molecular interactions help naive T lymphocytes migrate into lymph nodes?
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L-selectin (on lymphocyte) with L-selectin ligand (on epithelial cells of HEVs)
CCR7 (on lymphocyte) with CCL19/CCL21 (chemokines expressed in the lymph node) |
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what molecular interactions help mature T lymphocytes migrate into peripheral tissues at sites of infection?
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E- or P-selectin (on endothelium) with E- or P-selectin ligand (on lymphocyte)
ICAM-1 or VCAM-1 (on endothelium) with LFA-1 or VLA-4 (on lymphocyte) CXCL10 (chemokine secreted at inflammation site) with CXCR3 (receptor on lymphocyte) |
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to what does CCR7 bind?
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CCR7 on naive lymphocytes binds to CCL19 or CCL21, chemokines secreted at lymph nodes, to aid the migration of lymphocytes across the HEV wall
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to what does LFA-1 bind?
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LFA-1 on mature lymphocytes binds to ICAM-1 on endothelial cells to aid in migration across the capillary endothelium
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to what does VLA-4 bind?
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VLA-4 on mature lymphocytes binds to VCAM-1 on endothelial cells to aid in migration across the capillary endothelium
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how do T lymphocytes enter the T-cell zones of lymph nodes?
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exit thymus, migrate to lymph nodes, enter T-cell zones through high endothelial venules (HEVs; specialized postcapillary venules)
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what is the physiologic function of MHC molecules?
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to display peptide fragments of proteins for recognition by antigen specific T cells
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on what chromosome are the genes for MHC molecules clustered?
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a small segment of chromosome 6
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what is another name for MHC complex?
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MHC = major histocompatibility complex
aka HLA (human leukocyte antigen) |
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where are class I MHC molecules expressed?
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all nucleated cells
platelets |
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what are the names of the three loci that encode class I MHC molecules?
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HLA-A
HLA-B HLA-C |
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what does a class I MHC molecule consist of?
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heterodimer of a polymorphic alpha (heavy) chain linked noncovalently to beta2-microglobulin (smaller, nonpolymorphic peptide)
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what are the three domains of the extracellular region of the alpha chain of class I MHC molecules? which domains form the cleft where peptides bind?
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alpha1
alpha2 alpha3 alpha1 and alpha2 are the domains that form the cleft where peptides bind |
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what is displayed by class I MHC molecules?
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peptides that are derived from proteins, such as viral antigens, that are located in the cytoplasm and usually produced in the cell
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what type of lymphocytes recognize class I MHC molecules?
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CD8+ T lymphocytes
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how are antigens loaded onto class I MHC molecules?
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cytoplasmic proteins are degraded in proteasomes and peptides are transported into the ER where the peptides bind to newly synthesized class I molecules
peptide-loaded MHC molecules associate with beta2-microglobulin to form a stable trimer that is transported to the cell surface |
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describe the interaction between an antigen presenting cell with class I MHC molecules and a T lymphocyte
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TCR recognizes the MHC-peptide complex
CD8 molecule, acting as a coreceptor, binds to the class I heavy chain (alpha3 domain) |
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what cells are said to be class I MHC-restricted?
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CD8+ T cells, because the CD8 molecule is highly specific for the heavy chain of the class I MHC molecule
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what is the name of the region where class II MHC molecules are encoded?
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HLA-D
subregions: - HLA-DP - HLA-DQ - HLA-DR |
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what does a class II MHC molecule consist of?
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heterodimer of a noncovalently associated alpha chain and beta chain
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what are the extracellular domains of the alpha and beta chains of class II MHC? which domains form the cleft which binds antigens?
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each chain has two extracellular domains:
- alpha1 - alpha2 - beta1 - beta2 alpha1 and beta1 are responsible for forming the antigen binding cleft |
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from where are antigens presented in class II MHC molecules derived?
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extracellular microbes and soluble proteins
(they are internalized into vesicles) |
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how is a class II MHC molecule loaded with antigen?
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proteins/extracellular microbes are internalized and proteolytically digested in endosomes or lysosomes
peptides resulting from proteolytic cleavage then associate with class II heterodimers in the vesicles stable peptide-MHC complexes are transported to the cell surface |
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describe the interaction between a class II MHC antigen presenting cell and a T lymphocyte
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TCR recognizes and binds the MHC:peptide complex
CD4 molecule, acting as a coreceptor, binds to the beta2 domain of the class II MHC |
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what cells are said to be class II MHC-restricted?
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CD4+ T lymphocytes
CD4 molecule is highly specific to the beta2 domain of the class II MHC molecule |
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in what cells are class II MHC molecules mainly expressed?
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cells that present ingested antigens and respond to T-cell help
- macrophages - B lymphocytes - dendritic cells |
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what proteins are encoded in the MHC locus, aside from class I and class II MHC molecules?
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some complement components
TNF lymphotoxin proteins involved in antigen presentation - proteasome components - peptide transporter - DM (class II-like molecule that facilitates binding to class II molecules) |
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what is an HLA haplotype?
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the combination of HLA alleles in each individual
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what is required for an individual to mount an immune response against a protein antigen?
|
he or she must have inherited the gene(s) for those MHC molecule(s) that can bind peptides derived from the antigen and present it to T cells
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what HLA allele is associated with ankylosing spondylitis?
|
HLA-B27
individuals who inherit this class I HLA allele have a 90-fold greater chance of developing ankylosing spondylitis than those who don't carry it |
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what HLA allele is associated with 21-hydroxylase deficiency?
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HLA-BW47
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what HLA allele is associated with hereditary hemochromatosis?
|
HLA-A
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what HLA alleles are associated with type I diabetes mellitus?
|
DR3 (increases risk five-fold)
DR4 (increases risk six-fold) DR3/DR4 (increases risk 20-fold) |
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what are interleukins?
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group of cytokines (secreted proteins/signaling molecules) that were first seen to be expressed by white blood cells (leukocytes)
mediate communications between leukocytes |
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what are colony-stimulating factors? what are their functions in immune and inflammatory responses?
|
cytokines that stimulate hematopoiesis
they increase leukocyte numbers they replace leukocytes that are consumed |
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what is the clonal selection hypothesis?
|
concept that lymphocytes specific for a large number of antigens exist before exposure to an antigen, and when an antigen enters, it selects the specific cells and activates them
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what is the estimate for the number of specificities in an adult?
what is the number of lymphocytes in an adult? |
10^7-10^9 different specificities
10^12 lymphocytes ***the number of lymphocytes specific for any one antigen is very small, probably less than 1/100,000 cells*** |
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what induces the innate immune response in the case of immunization with a protein antigen?
|
the adjuvant given with the antigen
**helps the APCs to express costimulator molecules** |
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what are the principal costimulators for T cells?
|
B7 proteins (CD80 and CD86) that are expressed on APCs and recognized by the CD28 receptor on naive T cells
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what is the process of T lymphocyte activation?
|
naive T lymphocytes -> activation by antigen and costimulators -> secrete IL-2 and expression of high-affinity IL-2 receptor -> proliferate and differentiate -> migrate ->recognize antigens displayed by macrophages/B cells -> express CD40L -> engage CD40 -> activate macrophages/B cells
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what is CD25?
|
the alpha subunit of the IL-2 receptor
it is produced by T lymphocytes when they are activated, and it increases the affinity of the IL-2R for IL-2 |
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what is the function of IL-2 in T lymphocytes?
|
IL-2 is a growth factor that acts on T lymphocytes and stimulates their proliferation, leading to an increase in the number of antigen-specific lymphocytes
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what molecules/interaction mediate(s) the functions of T helper cells?
|
CD40:CD40L
CD40 is expressed on macrophages and B lymphocytes CD40L is expressed on activated T helper cells |
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what cytokines are produced by TH1 cells?
|
IFN-gamma
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what cytokines induce the differentiation of CD4+ cells into TH1 cells?
|
IFN-gamma
IL-12 |
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what immunological reactions are triggered by TH1 cells?
|
macrophage activation
stimulation of IgG antibody production |
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against what organisms are TH1 cells useful?
|
intracellular microbes
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in what types of disease are TH1 involved?
|
immune-mediated chronic inflammatory diseases (often autoimmune)
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what cytokines are produced by TH2 cells?
|
IL-4
IL-5 IL-13 |
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what cytokines induce the differentiation of CD4+ cells into TH2 cells?
|
IL-4
|
|
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what immunological reactions are triggered by TH2 cells?
|
stimulation of IgE production
activation of mast cells and eosinophils |
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against what organisms are TH2 cells useful?
|
helminthic parasites
|
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in what type of disease do TH2 cells play a role?
|
allergies
|
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what type of cytokines are produced by TH17 cells?
|
IL-17
IL-22 chemokines |
|
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what cytokines induce the differentiation of CD4+ cells into TH17 cells?
|
TGF-beta
IL-6 IL-1 IL-23 |
|
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what immunological reactions are triggered by TH17 cells?
|
recruitment of neutrophils
recruitment of monocytes |
|
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against what types of organisms are TH17 cells useful?
|
extracellular bacteria, fungi
|
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what is the role of TH17 cells in disease?
|
immune-mediated chronic inflammatory diseases (often autoimmune)
|
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what is the result of combined activation of macrophages with IFN-gamma and CD40?
|
induction of microbicidal substances, leading to the destruction of ingested microbes
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what are the functions of IL-4?
|
induce differentiation of CD4+ cells into TH2 cells
stimulate B cells to differentiate into IgE-secreting plasma cells |
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what is the function of IL-5?
|
activates eosinophils
|
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how do the antigen binding sites of secreted antibodies compare to B cell receptors?
|
each plasma cell secretes antibodies that have the same antigen binding site as the cell surface antibodies (BCRs) that first recognized the antigen
|
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secretion of what type of antibody is stimulated by polysaccharide and lipid antigens?
|
mainly IgM antibody
|
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secretion of what types of antibodies is stimulated by protein antigens?
|
IgG
IgA IgE |
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what is affinity maturation?
|
the process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response
|
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where do the processes of isotype switching and affinity maturation occur?
|
mainly in germinal centers, which are formed by proliferating B cells, especially in T cell-dependent responses to protein antigens
|
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what cells express receptors for the Fc tails of IgG?
|
neutrophils
macrophages |
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what types of antibodies activate the complement system by the classical pathway?
|
IgG
IgM |
|
|
which T helper cells induce the production of most opsonizing and complement-fixing IgG antibodies?
|
TH1 cells (respond to many bacteria and viruses)
|
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where is IgA secreted? what is its function?
|
secreted from mucosal epithelia
neutralizes microbes in the lumens of the respiratory and GI tracts (and other mucosal tissues) |
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which antibody can travel across the placenta? how?
|
IgG
active transport |
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what is the purpose of IgG travelling across the placenta?
|
protects the newborn until the immune system becomes mature
|
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what is the main method by which IgE and eosinophils cooperate to kill parasites?
|
release of eosinophil granule contents that are toxic to the worms
|
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by what type of helper T cells is the response to helminths orchestrated?
|
TH2 cells
|
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what is the half-life of most circulating IgG antibodies?
|
about 3 weeks
|
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what happens to most effector lymphocytes, induced by an infectious pathogen, after the microbe is eliminated?
|
die by apoptosis
|
|
|
what is the advantage to memory cells?
|
more numerous than the naive cells specific for any antigen that are present before encounter with that antigen
|
|
|
what are the prototypic disorders of immediate (type I) hypersensitivity reactions?
|
anaphylaxis
allergies bronchial asthma |
|
|
what are the prototypic disorders of antibody-mediated (type II) hypersensitivity reactions?
|
autoimmune hemolytic anemia
goodpasture syndrome |
|
|
what are the prototypic disorders of immune complex-mediated (type III) hypersensitivity reactions?
|
systemic lupus erythematosus
some forms of glomerulonephritis serum sickness arthus reaction |
|
|
what are the prototypic disorders of cell-mediated (type IV) hypersensitivity reactions?
|
contact dermatitis
multiple sclerosis type I diabetes rheumatoid arthritis inflammatory bowel disease tuberculosis |
|
|
what are the immune mechanisms of immediate (type I) hypersensitivity reaction?
|
production of IgE antibody -> immediate release of vasoactive amines and other mediators from mast cells -> recruitment of inflammatory cells
|
|
|
what are the immune mechanisms of antibody-mediated (type II) hypersensitivity reaction?
|
production of IgG, IgM antibodies -> binds to antigen on target cell or tissue -> phagocytosis or lysis of target cell by activated complement or Fc receptors -> recruitment of leukocytes
|
|
|
what are the immune mechanisms of immune complex-mediated (type III) hypersensitivity reaction?
|
deposition of antigen-antibody complexes -> complement activation -> recruitment of leukocytes by complement products and Fc receptors -> release of enzymes and other toxic molecules
|
|
|
what are the immune mechanisms of cell-mediated (type IV) hypersensitivity reaction?
|
activated T lymphocytes ->
i) release of cytokines -> inflammation and macrophage activation ii) T cell-mediated cytotoxicity |
|
|
what are the pathologic lesions associated with immediate (type I) hypersensitivity reactions?
|
vascular dilation
edema smooth muscle contraction mucus production tissue injury inflammation |
|
|
what are the pathologic lesions associated with antibody-mediated (type II) hypersensitivity reactions?
|
phagocytosis and lysis of cells
inflammation functional derangements without cell/tissue injury (in some diseases) |
|
|
what are the pathologic lesions associated with immune complex-mediated (type III) hypersensitivity reactions?
|
inflammation
necrotizing vasculitis (fibrinoid necrosis) |
|
|
what are the pathologic lesions associated with cell-mediated (type IV) hypersensitivity reactions?
|
perivascular cellular infiltrates
edema granuloma formation cell destruction |
|
|
what is a type I hypersensitivity reaction?
|
aka immediate hypersensitivity reaction
rapid immunologic reaction occurring within minutes after the combination of an antigen with antibody-bound mast cells in individuals previously sensitized to antigen |
|
|
which type of hypersensitvity reactions are called allergic reactions?
|
type I (immediate)
|
|
|
what are the two phases of a type I hypersensitivity reaction?
|
type I = immediate
immediate phase (initial rxn) - vasodilation, vascular leakage, smooth muscle spasm, and glandular secretions (sets in 5-30 minutes after exposure and lasts 60 minutes) late-phase reaction - infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal epithelial damage (sets in 2-24hrs after exposure and lasts several days) |
|
|
what is the mediator in type I hypersensitivity reactions?
|
type I = immediate
IgE antibody-dependent activation of mast cells |
|
|
from where are mast cells derived?
|
blood marrow
|
|
|
where are mast cells abundant?
|
near blood vessels and nerves and in subepithelial tissues
(common sites of type I hypersensitivity reactions) |
|
|
how are mast cells activated?
|
cross-linking of high-affinity IgE Fc receptors
complement components (C5a, C3a) |
|
|
what role do TH2 cells play in the initiation and propagation of type I hypersensitivity reactions?
|
type I = immediate
stimulate IgE production and promote inflammation |
|
|
what cytokines, released from TH2 cells, are important for type I hypersensitivity reactions?
|
type I = immediate
IL-4 - stimulates class switch of B cells to IgE, promotes development of addl. TH2 cells IL-5 - develops and activates eosinophils IL-13 - enhances IgE production and acts on epithelial cells to stimulate mucus secretion |
|
|
what is the high affinity receptor for IgE, that is expressed by mast cells and basophils?
|
FcepsilonRI
specific, high-affinity receptor for Fc portion of IgE |
|
|
what happens when two Fcepsilon receptors are cross-linked?
|
the bridging activates signal transduction pathways from the cytoplasmic portion of the receptors which cause degranulation (release of primary mediators) and synthesis/release of secondary mediators
|
|
|
what is a primary mediator?
|
a preformed mediator that is stored in cytoplasmic vesicles
|
|
|
what is a secondary mediator?
|
a mediator that must be synthesized de novo after the activation of a cell in order to be secreted
|
|
|
what are the three categories of preformed mediators in mast cells?
|
i) vasoactive amines (histamine)
ii) enzymes (proteases and acid hydrolases) iii) proteoglycans (heparin, chondroitin sulfate) |
|
|
what are the effects of histamine?
|
intense smooth muscle contraction
increased vascular permeability increased mucus secretions by nasal, bronchial, and gastric glands |
|
|
what type of enzymes are chymase and tryptase?
|
neutral proteases
|
|
|
what is the function of neutral proteases in the granules of mast cells?
|
generate kinins and activated components of complement by acting on their precursor proteins (in the plasma)
|
|
|
what is the function of proteoglycans in the granules of mast cells?
|
package and store the amines in the granules
|
|
|
what is phospholipase A2?
|
an enzyme that acts on membrane phospholipids to yield arachidonic acid
|
|
|
what are the lipid mediators produced by mast cells?
|
leukotrienes B4, C4 and D4
prostaglandin D2 platelet-activating factor |
|
|
what are the most potent vasoactive and spasmogenic agents known?
|
leukotrienes C4 and D4
|
|
|
what is important about LTB4?
|
highly chemotactic for neutrophils, eosinophils, and monocytes
|
|
|
what is the most abundant lipid mediator produced in mast cells by the COX pathway?
|
prostaglandin D2
|
|
|
what are the effects of prostaglandin D2?
|
intense bronchospasm
increased mucus secretion |
|
|
what are the effects of platelet activating factor?
|
platelet aggregation
histamine release bronchospasm increased vascular permeability vasodilation chemotactic for neutrophils and eosinophils |
|
|
how is PAF metabolism similar to/different from other lipid mediators?
|
similar - production triggered by the activation of phospholipase A2
different - not a product of arachidonic acid |
|
|
what cytokines are produced/released by mast cells?
|
TNF
IL-1 chemokines IL-4 |
|
|
what cytokines promote/favor the survival of eosinophils in tissues?
|
IL-3
IL-5 granulocyte-macrophage colony-stimulating factor (GM-CSF) |
|
|
which cytokines activate eosinophils in tissues?
|
IL-5 - most potent eosinophil-activating cytokine known
|
|
|
what is atopy?
|
predisposition to develop localized immediate (type I) hypersensitivity reactions to a variety of inhaled and ingested allergens
|
|
|
what is different about atopic individuals (compared to the general population)?
|
atopic individuals tend to have higher serum IgE levels, and more IL-4 producing TH2 cells
|
|
|
what is the hygiene hypothesis?
|
reduced exposure to microbes resets the immune system in such a way that TH2 responses develop more readily against common environmental antigens
|
|
|
what are the characteristic features of systemic anaphylaxis?
|
vascular shock
widespread edema difficulty breathing |
|
|
describe the process of systemic anaphylaxis
|
within minutes after exposure, itching, hives, and skin erythema appear, followed shortly thereafter by a striking contraction of respiratory bronchioles and respiratory distress
laryngeal edema results in hoarseness and further compromises breathing vomiting, abdominal cramps, diarrhea, and laryngeal obstruction follow patient may go into shock and die within the hour |
|
|
what are the specific local immediate hypersensitivity reactions?
|
urticaria
angioedema allergic rhinitis (hay fever) bronchial asthma |
|
|
what is type II hypersensitivity?
|
type II = antibody-mediated
caused by antibodies that react with antigens present on cell surfaces or in the extracellular matrix |
|
|
how are cells opsonized with IgG antibodies recognized?
|
phagocyte Fc receptors
|
|
|
what is the effect of IgG and IgM antibodies, deposited on cell surfaces, on complement?
|
activate the complement system by the classical pathway
|
|
|
with what type of cells is the membrane attack complex useful?
|
cells that have thin cell walls
i.e. Neisseria bacteria |
|
|
what is antibody-dependent cellular cytotoxicity?
|
a mechanism of cell-mediated immunity whereby an effector cell of the immune system actively lyses a target cell that has been bound by specific antibodies (cell lysis w/o phagocytosis)
|
|
|
what cells mediate ADCC?
|
ADCC = antibody-dependent cellular cytotoxicity
mediated by monocytes, neutrophils, eosinophils, and NK cells |
|
|
in what situations do type II hypersensitivity reactions occur?
|
type II = antibody-mediated
1) transfusion reactions 2) erythroblastosis fetalis 3) autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia 4) certain drugs that act as "haptens" by attaching to molecules of red cells |
|
|
how do transfusion reactions trigger type II hypersensitivity?
|
if donor and recipient are incompatible, the transfused cells will be opsonized by preformed antibody in the host
|
|
|
what is erythroblastosis fetalis?
|
aka hemolytic disease of the newborn
a type II (antibody-mediated) hypersensitivity reaction presence of an antigenic difference between the mother and the fetus, and IgG antibodies that cross the placenta and cause the destruction of fetal red cells |
|
|
what is a hapten?
|
a small molecule that can elicit an immune response only when attached to a large carrier such as a protein (or surface molecule of red blood cells); the carrier may be one that also does not elicit an immune response by itself
(antibodies are produced against the drug-protein complex) |
|
|
autoimmune hemolytic anemia
|
type II hypersensitivity reaction
target antigen: red cell membrane proteins (Rh blood group antigens, I antigen) mechanism: opsonization and phagocytosis of red cells manifestations: hemolysis, anemia |
|
|
autoimmune thrombocytopenic purpura
|
type II hypersensitivity reaction
target antigen: platelet membrane proteins (GpIIb:IIIa integrin) mechanism: opsonization and phagocytosis of platelets manifestations: bleeding |
|
|
pemphigus vulgaris
|
type II hypersensitivity reaction
target antigen: proteins in intercellular junctions of epidermal cells (epidermal cadherin) mechanism: antibody-mediated activation of proteases, disruption of intercellular adhesions manifestations: skin vesicles (bullae) |
|
|
vasculitis caused by ANCA (antineutrophil cytoplasmic antibodies)
|
type II hypersensitivity reaction
target antigen: neutrophil granule proteins, presumably released from activated neutrophils mechanism: neutrophil degranulation and inflammation manifestations: vasculitis |
|
|
goodpasture syndrome
|
type II hypersensitivity reaction
target antigen: noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli mechanism: complement- and Fc receptor-mediated inflammation manifestations: nephritis, lung hemorrhage |
|
|
acute rheumatic fever
|
type II hypersensitivity reaction
target antigen: streptococcal cell wall antigen (antibody cross-reacts with myocardial antigen) mechanism: inflammation, macrophage activation manifestations: myocarditis, arthritis |
|
|
myasthenia gravis
|
type II hypersensitivity reaction
target antigen: acetylcholine receptor mechanism: antibody inhibits ACh binding, down-modulates receptors manifestations: muscle weakness, paralysis |
|
|
graves disease
|
type II hypersensitivity reaction
target antigen: TSH receptor mechanism: antibody-mediated stimulation of TSH receptors manifestations: hyperthyroidism |
|
|
insulin-resistant diabetes
|
type II hypersensitivity reaction
target antigen: insulin receptor mechanism: antibody inhibits binding of insulin manifestations: hyperglycemia, ketoacidosis |
|
|
pernicious anemia
|
type II hypersensitivity reactions
target antigen: intrinsic factor of gastric parietal cells mechanism: neutralization of intrinsic factor, decreased absorption of vitamin B12 manifestation: abnormal erythropoiesis, anemia |
|
|
what causes the resultant injury when antibodies are deposited in fixed tissues, such as basement membranes and extracellular matrix?
|
inflammation
|
|
|
systemic lupus erythematosus
|
type III hypersensitivity reaction
antigen: nuclear antigens manifestations: nephritis, skin lesions, arthritis |
|
|
poststreptococcal glomerulonephritis
|
type III hypersensitivity reaction
antigen: streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane manifestations: nephritis |
|
|
polyarteritis nodosa
|
type III hypersensitivity reaction
antigen: hepatitis B virus antigens (in some cases) manifestations: systemic vasculitis |
|
|
reactive arthritis
|
type III hypersensitivity reaction
antigen: bacterial antigens (e.g. Yersinia) manifestations: acute arthritis |
|
|
serum sickness
|
type III hypersensitivity reaction
antigen: various proteins, e.g. foreign serum protein (horse anti-thymocyte globulin) manifestations: arthritis, vasculitis, nephritis |
|
|
arthus reaction (experimental)
|
type III hypersensitivity reaction
antigen: various foreign proteins manifestations: cutaneous vasculitis |
|
|
what are type III hypersensitivity reactions?
|
aka immune complex-mediated
antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition; the pathologic reaction is initiated when antigen combines with antibody w/in the circulation, and these are deposited typically in vessel walls |
|
|
what is the prototypic systemic immune complex disease?
|
serum sickness
|
|
|
how are immune complexes formed?
|
the introduction of a protein antigen triggers an immune response that results in the formation of antibodies, typically about a week after the injection of the protein
the antibodies are secreted into the blood, where they react with antigen still present in the circulation and form antigen-antibody complexes |
|
|
what complexes are the most pathogenic?
|
those of medium size, formed in slight antigen excess
|
|
|
where do complexes typically deposit?
|
blood vessel walls
organs where blood is filtered at high pressure to form other fluids: - glomeruli (filtered to form urine) - joints (filtered to form synovial fluid) |
|
|
what are the clinical features of a general type III hypersensitivity reaction?
|
type III = immune complex-mediated
fever urticaria joint pains (arthralgias) lymph node enlargement proteinuria |
|
|
what happens once immune complexes are deposited in tissues?
|
they initiate an acute inflammatory reaction
|
|
|
what induces the pathologic lesions of immune complex disorders?
|
complement-fixing antibodies (IgG and IgM)
antibodies that bind to leukocyte Fc receptors (some subclasses of IgG) |
|
|
what is the principal morphologic manifestation of immune complex-mediated hypersensitivity?
|
type III = immune complex-mediated
acute necrotizing vasculitis, with necrosis of the vessel wall and intense neutrophilic infiltration |
|
|
what is fibrinoid necrosis?
|
a form of necrosis, or tissue death, in which there is accumulation of amorphous, basic, proteinaceous material in the tissue matrix with a staining pattern reminiscent of fibrin
associated with type III hypersensitivity reactions |
|
|
what happens if a type III hypersensitivity reaction results from a single large exposure to antigen?
|
the lesions tend to resolve as a result of catabolism of the immune complexes
|
|
|
what is the arthus reaction?
|
a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin
|
|
|
what are type IV hypersensitivity reactions?
|
type IV = cell-mediated
aka delayed-type hypersensitivity reactions reactions initiated by antigen-activated (sensitized) T lymphocytes, including CD4+ and CD8+ T cells |
|
|
what cellular component dominates the inflammatory reaction associated with TH1 cells?
|
macrophages
|
|
|
what cellular component dominates the inflammatory reaction associated with TH17 cells?
|
neutrophil
|
|
|
what cytokine can be produced by dendritic cells and macrophages to induce differentiation of CD4+ T cells to the TH1 subset?
|
IL-12
IFN-gamma |
|
|
what cytokines can be produced by dendritic cells and macrophages to induce differentiation of CD4+ T cells to the TH17 subset?
|
IL-1
IL-6 IL-23 **work in collaboration with TGF-beta, which is produced by many cell types** |
|
|
what cytokine is a close relative of IL-12?
|
IL-23
|
|
|
type I diabetes mellitus
|
type IV hypersensitivity reaction
antigen: pancreatic islet beta cells (insulin, glutamic acid decarboxylase) manifestations: insulitis, destruction of beta cells, diabetes |
|
|
multiple sclerosis
|
type IV hypersensitivity reaction
antigen: protein antigens in CNS myelin (myelin basic protein, proteolipid protein) manifestations: demyelination in CNS with perivascular inflammation; paralysis, ocular lesions |
|
|
rheumatoid arthritis
|
type IV hypersensitivity reaction
antigen: unknown antigen in joint synovium (type II collagen?) manifestations: chronic arthritis with inflammation, destruction of articular cartilage and bone |
|
|
crohn disease
|
type IV hypersensitivity reaction
antigen: unknown antigen; role for commensal bacteria manifestations: chronic intestinal inflammation, obstruction |
|
|
peripheral neuropathy (Guillain-Barre syndrome)
|
type IV hypersensitivity reaction
antigen: protein antigens of peripheral nerve myelin manifestations: neuritis, paralysis |
|
|
contact sensitivity (dermatitis)
|
type IV hypersensitivity reaction
antigen: various environmental antigens (e.g. poison ivy) manifestations: skin inflammation with blisters |
|
|
how are IFN-gamma-activated macrophages altered?
|
augmented ability to phagocytose and kill microbes
increased expression of class II MHC molecules secrete TNF, IL-1, and chemokines (promote inflammation) produce more IL-12 (enhance TH1 response) |
|
|
what cytokines are produced by TH17 cells? what are their functions?
|
IL-17, IL-22, chemokines
collectively, these recruit neutrophils and monocytes IL-21 this amplifies the TH17 response |
|
|
what is the classic example of delayed type hypersensitivity?
|
type IV = delayed type = cell-mediated
tuberculin reaction |
|
|
what is the tuberculin reaction?
|
purified protein derivative (PPD/tuberculin), a protein containing antigen of the tubercle bacillus, is injected subcutaneously
in a previously sensitized individual, reddening and induration of the site appear in 8-12 hours, reach a peak in 24-72 hours, and thereafter slowly subside |
|
|
what happens to activated macrophages in a situation where there is a persistent or nondegradable antigen?
|
they often undergo a morphologic transformation into epithelium-like cells and are then referred to as epitheloid cells
|
|
|
what is a granuloma?
|
a microscopic aggregation of epitheloid cells, usually surrounded by a collar of lymphocytes
|
|
|
with what is granulomatous inflammation typically associated?
|
strong T-cell activation with cytokine production
|
|
|
what is contact dermatitis?
|
common example of tissue injury resulting from delayed-type hypersensitivity reactions
e.g. poison ivy contact -> vesicular dermatitis |
|
|
what is urushiol?
|
the antigenic component of poison ivy or poison oak
|
|
|
how is a virus infected cell recognized by CD8+ T lymphocytes?
|
viral peptides are displayed by class I MHC molecules ant the complex is recognized by the TCR of the CD8+ T lymphocytes
|
|
|
what is the principal mechanism of T cell-mediated killing of target cells?
|
perforins - forms a pore in target cell's plasma membrane
granzymes - enter through pores, cleave and activate caspases (induce apoptosis) |
|
|
what are the two methods of T cell-mediated killing of target cells?
|
perforin/granzymes
FasL |
|
|
what is the function of perforin?
|
inserts itself into a target cell's plasma membrane and forms a pore
|
|
|
what is the function of granzymes?
|
enter target cells through pores and cleave caspases (triggering apoptosis)
|
|
|
what is the function of FasL?
|
FasL is present on CTLs
it binds to Fas expressed on target cells and trigger apoptosis in that cell |
|
|
what cytokines do CD8+ T cells produce?
|
IFN-gamma
|
|
|
what are two non-pathological instances where autoantibodies can be seen?
|
serum of older individuals (who appear normal)
innocuous autoantibodies after damage to tissue (may help to remove tissue breakdown products) |
|
|
what are the three criteria that should be met to qualify something as autoimmune?
|
1) presence of an immune reaction specific to some self-antigen or self-tissue
2) evidence that such a reaction is not secondary to tissue damage, but is of primary pathogenic significance 3) absence of another well-defined cause of the disease |
|
|
what is immunological tolerance?
|
the phenomenon of unresponsiveness to an antigen as a result of exposure of lymphocytes to that antigen
|
|
|
what is self-tolerance?
|
lack of responsiveness to an individual's own antigens
|
|
|
what is central tolerance?
|
process by which immature self-reactive T- and B-lymphocyte clones that recognize self antigens during their maturation in generative (central) lymphoid organs are killed or rendered harmless
|
|
|
what is peripheral tolerance?
|
silencing of potentially autoreactive T and B cells in peripheral tissues
- anergy - suppression by regulatory T cells - deletion by activation-induced cell death |
|
|
what is negative selection?
|
process by which immature lymphocytes that encounter and react to self-antigens die by apoptosis
|
|
|
what protein stimulates the expression of some "peripheral tissue-restricted" self-antigens in the thymus?
|
AIRE (autoimmune regulator)
critical for deletion of immature T cells specific for self-antigens |
|
|
what is AIRE?
|
autoimmune regulator
a protein that stimulates the expression of some "peripheral tissue-restricted" self-antigens in the thymus critical protein for deletion of self-reactive immature T cells |
|
|
what results from mutations in AIRE?
|
AIRE = autoimmune regulator
autoimmune polyendocrinopathy |
|
|
what happens when immature T cells strongly recognize self-antigens in the thymus?
|
die by apoptosis
aka negative selection aka deletion |
|
|
what happens when immature B cells strongly recognize self-antigens in the bone marrow?
|
reactivate machinery of antigen receptor gene rearrangement, and begin to express new antigen receptors that aren't self-reactive
OR die by apoptosis (aka negative selection, or deletion) |
|
|
what is receptor editing?
|
During maturation in the bone marrow, B cells are tested for interaction with self antigens, which is called negative selection. If the maturing B cells strongly interact with these self antigens, they undergo death by apoptosis. Negative selection is important to avoid the production of B cells that could cause autoimmune diseases. They can avoid apoptosis by modifying the sequence of light chain V and J genes (components of the antigen receptor) so that it has a different specificity and may not recognize self antigens anymore. This process of changing the specificity of the immature B cell receptor is called receptor editing.
|
|
|
what is anergy?
|
prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens under certain conditions (absence of costimulators)
|
|
|
what happens to a T cell if its antigen is presented by cells that do not have CD80/CD86 (B7 proteins)?
|
a negative signal is delivered and the cell becomes anergic
|
|
|
how can T cells lose their ability to trigger biochemical signals from the TCR complex?
|
a mechanism of creating anergy
ubiquitin ligases are activated leading to proteolytic degradation of receptor-associated signaling proteins |
|
|
what are the two inhibitory receptors of T cells?
|
CTLA-4 (similar to CD28, in that it binds to B7 molecules, CD80 and CD86, but serves the opposite function)
PD-1 |
|
|
what are the two mechanisms by which a T cell can become anergic?
|
lose ability to trigger biochemical signals from TCR complex
receive an inhibitory signal from receptors that are structurally homologous to CD28, but serve opposite functions (inhibit rather than activate) |
|
|
what are polymorphisms in the CTLA4 gene associated with?
|
autoimmune endocrine diseases in humans
|
|
|
how does B cell anergy occur?
|
if B cells encounter/react to self-antigen in peripheral tissues, especially in the absence of specific helper T cells, the B cells become unable to respond to subsequent antigenic stimulation
(also may be excluded from lymphoid follicles resulting in their death) |
|
|
where do regulatory T cells develop?
|
mainly in the thymus (as a result of recognition of self-antigens)
also in peripheral lymphoid tissues |
|
|
what are the best-defined regulatory T cells?
|
CD4+ cells that constitutively express CD25 (alpha chain of IL-2 receptor) and Foxp3 (transcription factor of the forkhead family)
|
|
|
what two things are required for development and maintenance of functional CD4+ regulatory T cells?
|
CD25 (alpha chain of IL-2R)
Foxp3 (transcription factor) |
|
|
what is the result of mutations in Foxp3?
|
severe autoimmunity
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) |
|
|
what is associated with mutations in the CD25 gene?
|
multiple sclerosis
|
|
|
how is the inhibitory activity of regulatory T cells mediated?
|
secretion of IL-10 and TGF-beta
(immunosuppressive cytokines which inhibit lymphocyte activation and effector functions) |
|
|
how does deletion by activation-induced cell death occur in T cells?
|
if T cells recognize self-antigens, they may express a pro-apoptotic member of the the Bcl family (Bim) without anti-apoptotic members of the Bcl family (Bcl-2, Bcl-x)
unopposed Bim triggers apoptosis by the mitochondrial pathway OR after binding to self-antigens, FasL and Fas (CD95) are co-expressed on the T cells, engage one another, and lead to elimination of the T cell |
|
|
how does deletion by activation-induced cell death occur in B cells?
|
FasL on T cells engaging Fas on the B cells
|
|
|
what is CD95?
|
aka Fas
a receptor molecule found on many cells that binds Fas ligand (FasL) FasL is found on activated CD8+ T cells and NK cells, and it triggers the induction of apoptosis in the target cell |
|
|
what are immune-privileged antigens?
|
antigens that are hidden (sequestered) from the immune system because the tissues in which they are located do not communicate with the blood and lymph
self-antigens in these tissues do not induce tolerance but fail to elicit immune responses |
|
|
what are the immune-privileged sites in the body?
|
testis
eye brain **it is difficult to induce immune responses into these sites** |
|
|
what happens if the antigens in immune-privileged sites are released as a consequence of trauma or infection?
|
immune response that leads to prolonged tissue inflammation and injury
examples: post-traumatic orchitis and uveitis |
|
|
among the genes known to be associated with autoimmunity, which has the greatest contribution?
|
HLA genes
|
|
|
what disorders are associated with polymorphisms in PTPN-22?
|
rheumatoid arthritis
type I diabetes **because these are so common, PTPN-22 is said to be the gene that is most frequently implicated in autoimmunity** |
|
|
what is PTPN-22?
|
a gene which encodes a protein tyrosine phosphatase
mutations in this gene are associated with rheumatoid arthritis and type I diabetes |
|
|
what disorder is associated with polymorphisms in the NOD-2 gene?
|
Crohn disease
(a form of inflammatory bowel disease, especially in certain ethnic populations) disease-associated variant is ineffective at sensing intestinal microbes, resulting in entry of and chronic inflammatory reactions to normally well-tolerated commensal bacteria |
|
|
what is NOD-2?
|
a cytoplasmic sensor of microbes expressed in epithelial and many other cells
mutations in this gene are associated with Crohn's disease |
|
|
with what disease are mutations in the IL-2 receptor (CD25) and IL-7 receptor alpha chains associated?
|
multiple sclerosis
other autoimmune diseases |
|
|
what is the normal negative-feedback mechanism to antibody production of B cells?
|
Fc receptor that recognizes IgG antibodies bound to antigens and switches off further antibody production
|
|
|
what are the two mechanisms which explain the link between infections and autoimmunity?
|
infections up-regulate expression of costimulators on APCs, even those presenting self-antigens (resulting in breakdown of anergy and activation of self-reactive T cells)
some microbes may express antigens that have the same amino acid sequences as self-antigens (immune responses against the microbial antigens may result in the activation of self-reactive lymphocytes) |
|
|
what is molecular mimicry?
give an example |
sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides
example: rheumatic heart disease (antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis) |
|
|
how do infections paradoxically protect against some autoimmune disease?
|
promote low-level IL-2 production (essential for maintaining regulatory T cells)
|
|
|
what is epitope spreading?
|
initially, an autoimmune response may have only one target antigen, but the damage caused by the initial response releases self-antigens and exposes epitopes of the antigens that are normally concealed from the immune system
immune response "spreads" to epitopes that weren't initially recognized |
|
|
why are systemic autoimmune diseases often classified as collagen vascular diseases?
|
they tend to involve blood vessels and connective tissues
|
|
|
what is the prototypical multisystem autoimmune disease?
|
systemic lupus erythematosus (SLE)
|
|
|
what is systemic lupus erythematosus?
|
autoimmune disease that is acute or insidious in its onset
it is a chronic, remitting and relapsing, often febrile illness characterized principally by injury to the skin, joints, kidney, and serosal membranes antinuclear antigen antibodies |
|
|
which gender is more affected by SLE?
|
women
develops in 1 in 700 women of childbearing age Female-to-Male ratio of 9:1 during childbearing years |
|
|
what renal symptoms are typical of SLE?
|
immune complex-mediated glomerulonephritis
|
|
|
what are antinuclear antibodies?
|
antibodies directed against nuclear antigens
1) DNA 2) histones 3) nonhistone proteins bound to RNA 4) nucleolar antigens |
|
|
what is the most widely used method for detecting ANAs?
|
ANAs - antinuclear antibodies
most commonly detected by indirect immunofluorescence |
|
|
in SLE, what type of antibodies are indicated by homogeneous or diffuse nuclear staining patterns?
|
antibodies to chromatin, histones, and, occasionally, dsDNA
|
|
|
in SLE, what type of antibodies are indicated by rim or peripheral staining patterns?
|
antibodies to double-stranded DNA
|
|
|
in SLE, what type of antibodies are indicated by speckled pattern staining?
|
antibodies to non-DNA nuclear constituents (Sm antigen, ribonucleoprotein, SS-A and SS-B reactive antigens)
|
|
|
in SLE, what type of antibodies are indicated by a nucleolar pattern of staining?
|
antibodies to RNA
reported most often in patients with systemic sclerosis |
|
|
what types of antibodies are virtually diagnostic of SLE?
|
antibodies to double-stranded DNA
antibodies to Smith (Sm) antigen |
|
|
in addition to antinuclear antibodies, what other types of antibodies are present in SLE?
|
antibodies against blood cells (red cells, platelets, lymphocytes)
antibodies against proteins in complex with phospholipids |
|
|
what are antiphospholipid antibodies?
|
antibodies against epitopes of plasma proteins (prothrombin, annexin V, beta2-glycoprotein I, protein S, protein C) that are revealed when the proteins are in complex with phospholipids
|
|
|
for what test do SLE patients often have a false positive result? why?
|
syphilis test
antibodies against the phopsholipid-beta2-glycoprotein complex also bind to cardiolipin antigen, which is used in syphilis serology |
|
|
what are lupus anticoagulants?
|
antibodies produced in SLE patients that interfere with in vitro clotting
paradoxical because these patients exhibit complication associated with a hypercoagulable state |
|
|
what complications do SLE patients face that are associated with a hypercoagulable state?
|
arterial and venous thromboses, that may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia
|
|
|
what is secondary antiphospholipid antibody syndrome?
|
presence of venous and arterial thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia
all has to be in association with lupus |
|
|
what is primary antiphospholipid antibody syndrome?
|
presence of venous and arterial thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia
all has to occur with no SLE present |
|
|
specific alleles of what gene locus have been linked to the production of anti-dsDNA, anti-Sm, and antiphospholipid antibodies?
|
HLA-DQ
|
|
|
how do TLRs figure into SLE?
|
nuclear DNA and RNA contained in immune complexes may activate B lymphocytes by engaging TLRs, thus B cells specific for nuclear antigens may get second signals from TLRs and may be activated, resulting in increased production of antinuclear antibodies
|
|
|
what is the effect of UV light on patients with SLE?
|
in many cases, it exacerbates the disease
may induce apoptosis in cells and may alter the DNA in such a way that it becomes immunogenic stimulates keratinocytes to produce IL-1, a cytokine known to promote inflammation |
|
|
what environmental factors can exacerbate or create SLE-like responses in people?
|
UV exposure
sex hormones drugs (hydralazine, procainamide, D-penicillamine |
|
|
what are LE cells?
|
any phagocytic leukocyte that has engulfed the denatured nucleus of an injured cell
|
|
|
what causes the most characteristic lesions in SLE?
|
immune complexes depositing in blood vessels, kidneys, connective tissue and skin
|
|
|
what is lupus nephritis?
|
immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or larger blood vessels
affects up to 50% of SLE patients |
|
|
what is mesangial lupus glomerulonephritis?
|
mesangial cell proliferation and immune complex deposition without involvement of glomerular capillaries
|
|
|
what is focal proliferative glomerulonephritis?
|
affected glomeruli may exhibit crescent formation, fibrinoid necrosis, proliferation of endothelial cells, mesangial cells, infiltrating leukocytes
fewer than 50% involvement of all glomeruli segmental (part of the glomerulus) or global (entire glomerulus) lesions hematuria and proteinuria follow found in 20-35% of patients with SLE |
|
|
what is the characteristic skin involvement of SLE?
|
erythema that affects the facial butterfly (malar) area (bridge of the nose and cheeks) in approximately 50% of patients
similar rash may also be seen on the extremities and trunk urticaria, bullae, maculopapular lesions, and ulcerations also occur |
|
|
what is seen histologically in the skin of SLE patients with the characteristic erythema?
|
vacuolar degeneration of the basal layer of the epidermis
variable edema and perivascular inflammation in the dermis deposition of Ig and complement along dermoepidermal junction |
|
|
what is the joint involvement in SLE?
|
nonerosive synovitis with little deformity, which contrasts with rheumatoid arthritis
|
|
|
how does SLE affect the cardiovascular system?
|
valvular abnormalities (primarily mitral and aortic valves)
valvular (Libman-Sacks) endocarditis |
|
|
what are the common splenic findings in SLE?
|
splenomegaly
capsular thickening follicular hyperplasia |
|
|
what are the common lung findings in SLE?
|
pleuritis and pleural effusions (50% of patients)
alveolar injury with edema and hemorrhage (less common) |
|
|
what is seen in the bone marrow in SLE patients?
|
LE (hematoxylin) bodies
can be in bone marrow or other organs strongly indicative of SLE |
|
|
what is the typical patient in a case of SLE?
|
a young woman with some (not necessarily all) of the following features:
- butterfly rash over face - fever - pain but no deformity in one or more peripheral joints - pleuritic chest pain - photosensitivity |
|
|
what are the neurologic/psychiatric symptoms sometimes seen with SLE?
|
psychosis
convulsions |
|
|
how are disease exacerbations of SLE treated?
|
corticosteroids or other immunosuppressive drugs
|
|
|
what are the 5- and 10-year survival rates for SLE?
|
90% 5 year survival
80% 10 year survival |
|
|
what are the most common causes of death in SLE patients?
|
most common causes of death are renal failure and intercurrent infections
|
|
|
what is chronic discoid lupus erythematosus?
|
disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare
characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border |
|
|
what is subacute cutaneous lupus erythematosus?
|
disease with predominant skin involvement
distinguished from chronic discoid lupus erythematosus by: - skin rash tends to be widespread, superficial, and nonscarring - most patients have mild systemic symptoms consistent with SLE - strong association with antibodies to SS-A antigen - strong association with HLA-DR3 genotype |
|
|
what drugs cause drug-induced lupus erythematosus?
|
hydralazine
procainamide isoniazid D-penicillamine |
|
|
what is drug-induced lupus erythematosus?
|
a lupus erythematosus-like syndrome that develops in patients receiving a variety of drugs
although multiple organs are affected, renal and central nervous system involvement is distinctly uncommon this disease remits after the withdrawal of the offending drug |
|
|
what is Sjogren syndrome?
|
a chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary glands
|
|
|
what is sicca syndrome?
|
aka Sjogren syndrome
decrease in tears and saliva as the result of lymphocytic infiltration and fibrosis of the lacrimal and salivary glands |
|
|
what is rheumatoid factor?
|
an antibody reactive with self-IgG
|
|
|
what are the most important antibodies in Sjogren syndrome?
|
antibodies against two ribonucleoprotein antigens
anti-SS-A (Ro) antibodies anti-SS-B (La) antibodies |
|
|
what are the extraglandular manifestations of Sjogren syndrome?
|
cutaneous vasculitis and nephritis
|
|
|
what is the initiating factor of Sjogren syndrome?
|
viral infection of the salivary glands, which causes local cell death and release of tissue self-antigens
self-reactive CD4+ T cells and B cells have to have escaped tolerance and be able to react the result is inflammation, tissue damage, and eventually fibrosis |
|
|
what is the candidate autoantigen for Sjogren syndrome?
|
alpha-fodrin (a cytoskeletal protein)
|
|
|
what is the earliest histologic finding in major and minor salivary glands in Sjogren syndrome?
|
periductal and perivascular infiltration
eventually the infiltrate becomes extensive, and in the larger salivary glands lymphoid follicles with germinal centers can be seen |
|
|
what are the clinical manifestations of Sjogren syndrome?
|
keratoconjunctivitis - blurring of vision, burning and itching, thick secretions accumulate in conjunctival sac
xerostomia - difficulty in swallowing solid foods, decrease in ability to taste, cracks/fissures in mouth, dryness of buccal mucosa dryness of nasal mucosa, epistaxis, recurrent bronchitis, and pneumonitis |
|
|
what is Mikulicz syndrome?
|
lacrimal and salivary gland enlargement from any cause (sarcoidosis, leukemia, lymphoma, etc.)
|
|
|
what is essential for the diagnosis of Sjogren syndrome?
|
biopsy of the lip to examine minor salivary glands
|
|
|
what is systemic sclerosis?
|
aka scleroderma
a chronic disease characterized by: 1) chronic inflammation thought to be the result of autoimmunity 2) widespread damage to small blood vessels 3) progressive interstitial and perivascular fibrosis in the skin and multiple organs |
|
|
what organs are commonly involved in systemic sclerosis?
|
skin - most commonly
GI tract kidneys heart muscles lungs |
|
|
what is the progression of systemic sclerosis?
|
aka sleroderma
in some patients, remains confined to skin for many years, but in most patients it progresses to visceral involvement with death from renal failure, cardiac failure, pulmonary insufficiency, or intestinal malabsorption |
|
|
what is the difference between diffuse scleroderma and limited scleroderma?
|
diffuse scleroderma - characterized by widespread skin involvement at onset, with rapid progression and early visceral involvement
limited scleroderma - skin involvement confined to fingers, forearms, and face; visceral involvement occurs late (more benign) |
|
|
what is CREST syndrome?
|
C - calcinosis
R - Raynaud's phenomenon E - esophageal dysmotility S - sclerodactyly T - telangiectasia acronym for the five main features of limited scleroderma (systemic sclerosis) |
|
|
what is calcinosis?
|
Calcinosis is the formation of calcium deposits in any soft tissue.
|
|
|
what is sclerodactyly?
|
a localized thickening and tightness of the skin of the fingers or toes
|
|
|
what is telangiectasia?
|
small dilated blood vessels near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter
commonly seen on the face around the nose, cheeks, and chin |
|
|
what two antinuclear antibodies are strongly associated with systemic sclerosis?
|
anti-DNA topoisomerase I antibodies (anti-Scl 70) - highly specific
anticentromere antibodies |
|
|
what is the abnormal immune response in scleroderma patients?
|
CD4+ T cells responding to an unidentified antigen accumulate in the skin and release cytokines (TGF-beta, IL-13) that activate inflammatory cells and fibroblasts
|
|
|
what vascular damage is found in patients with scleroderma?
|
intimal proliferation of digital arteries (100% of pts)
capillary dilation with leaking, and destruction nailfold capillary loops are distored early in the course of disease, and later disappear |
|
|
what is seen on vascular smooth muscle cells in patients with scleroderma?
|
increased expression of adrenergic receptors
|
|
|
what are the abnormalities that culminate in the progressive fibrosis characteristic of systemic sclerosis (scleroderma)?
|
actions of fibrogenic cytokines produced by infiltrating leukocytes
hyperresponsiveness of fibroblasts to cytokines scarring following upon ischemic damage caused by the vascular lesions primary abnormality in collagen production |
|
|
what happens to the fingers in scleroderma?
|
sclerotic atrophy of the skin
they take on a tapered, clawlike appearance with limitation of motion in the joints |
|
|
what happens to the skin in scleroderma patients?
|
diffuse, sclerotic atrophy beginning in fingers, and distal regions of upper extremities
increasing fibrosis of the dermis, which becomes tightly bound to the subcutaneous structures loss of blood supply may lead to cutaneous ulcerations and to atrophic changes in the terminal phalanges |
|
|
what happens to the alimentary tract in scleroderma?
|
progressive atrophy and collagenous fibrous replacement of the muscularis may develop at any level of the gut but are most severe in the esophagus
lower 2/3 of esophagus often develops a rubber-hose inflexibility dysfunction of the LES gives rise to gastroesophageal reflux leading to barrett metaplasia and strictures loss of villi and microvilli in the small bowel is the anatomic basis for the malabsorption syndrome sometimes encountered |
|
|
what happens to the musculoskeletal system in systemic sclerosis?
|
inflammation of synovium in the early stages, followed later by fibrosis
joint destruction is rare |
|
|
what renal changes are noted in systemic sclerosis (scleroderma)?
|
intimal thickening of interlobular arteries as a result of mucinous or finely collagenous material (stains histochemically for glycoprotein and acid mucopolysaccharides)
|
|
|
what are the changes noted in the lungs in systemic sclerosis patients?
|
pulmonary hypertension and interstitial fibrosis
pulmonary vasospasm, secondary to pulmonary vascular endothelial dysfunction |
|
|
what are the changes noted in the heart in systemic sclerosis patients?
|
pericarditis with effusion and myocardial fibrosis, along with thickening of intramyocardial arterioles
|
|
|
what is the female:male ratio for systemic sclerosis?
|
3:1
peak incidence in the 50-60 year age group |
|
|
with what three autoimmune diseases does systemic sclerosis share many features?
|
SLE
RA polymyositis |
|
|
what are the distinctive features of systemic sclerosis?
|
skin thickening
raynaud's phenomenon dysphagia (esophageal fibrosis) |
|
|
what is the most ominous manifestation of systemic sclerosis?
|
malignant hypertension, with subsequent development of fatal renal failure
|
|
|
what are inflammatory myopathies?
|
uncommon, heterogeneous group of disorders characterized by injury and inflammation of mainly the skeletal muscles, which are probably immunologically mediated
- dermatomyositis - polymyositis - inclusion-body myositis |
|
|
what is mixed connective tissue disease?
|
disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis
characterized by high titers of antibodies to ribonucleoprotein particle-containing U1 ribonucleoprotein typically shows modest renal involvement and good response to corticosteroids |
|
|
what are two of the more serious complications that arise from mixed connective tissue disease?
|
pulmonary hypertension
renal disease |
|
|
what is polyarteritis nodosa?
|
disease characterized by necrotizing inflammation of the walls of blood vessels with immunological pathogenetic mechanism
noninfectious vasculitis |
|
|
what is rejection?
|
recipient's immune system recognizes a graft as being foreign and attacks it
|
|
|
what is cellular rejection?
|
T cell-mediated graft rejection
involves destruction of graft cells by CD8+ CTLs and delayed hypersensitivity reactions triggered by activated CD4+ helper T cells |
|
|
what are the major antigenic differences between a donor and a recipient that result in rejection of transplants?
|
HLA alleles (highly polymorphic)
|
|
|
what is the direct pathway of graft rejection?
|
T cells of the transplant recipient recognize donor MHC molecules on the surface of APCs (dendritic cells) in the graft
|
|
|
what are the most important APCs for initiating the direct antigraft response?
|
donor dendritic cells carried in the organ
express high levels of class I and II MHC molecules and high levels of costimulatory molecules |
|
|
describe the process of the direct pathway of graft rejection
|
host T cells encounter donor dendritic cells in grafted organ or after the dendritic cells have migrated to the draining lymph nodes
T cells are activated, differentiate, and migrate to graft CD8+ T cells kill grafts and CD4+ T cells differentiate into TH1 cells |
|
|
what is the effect of cytokines secreted by activated CD4+ T cells?
|
trigger a delayed hypersensitivity reaction in the graft, resulting in increased vascular permeability and local accumulation of mononuclear cells (lymphocytes, macrophages), and graft injury caused by the activated macrophages
|
|
|
what is the interaction that occurs between recipient T cells and donor APCs?
|
allogeneic MHC molecules, with their bound peptides, resemble the self-MHC-foreign peptide complexes that are recognized by self-MHC-restricted T cells
cross-reaction of T cells selected to recognize self-MHC plus foreign peptides |
|
|
what is the indirect pathway of graft rejection?
|
peptides derived from the donor tissue are presented by the host's own MHC molecules
|
|
|
what type of T cells are generated by the indirect pathway of graft rejection?
|
CD4+ T cells that enter the graft and recognize graft antigens being displayed by host APCs
CD8+ CTLs that may be generated cannot directly recognize or kill graft cells, because these CTLs recognize graft antigens presented by the host's APCs |
|
|
what is the principal mechanism of cellular rejection in the indirect pathway of graft rejection?
|
T-cell cytokine production and delayed hypersensitivity
direct killing by CTLs is not possible, because they cannot directly recognize or kill graft cells |
|
|
what is the major pathway in acute cellular rejection?
|
direct pathway
donor APCs present to recipient T cells, activating CTLs that can kill graft cells directly |
|
|
what is the major pathway in chronic rejection?
|
indirect pathway
|
|
|
what is humoral rejection?
|
production of antibodies against alloantigens in the graft
|
|
|
what is the hyperacute rejection form of humoral rejection?
|
preformed antidonor antibodies are present in the circulation of the recipient
- recipient who has previously rejected a kidney transplant - multiparous women who develop anti-HLA antibodies against paternal antigens shed from fetus - prior blood transfusions |
|
|
what is the initial target of the antibodies involved in rejection?
|
graft vasculature
acute humoral rejection is usually manifested by vasculitis (rejection vasculitis) |
|
|
what are the classifications of rejection?
|
hyperacute rejection
acute cellular rejection acute humoral rejection chronic rejection |
|
|
what is hyperacute rejection?
|
rejection within minutes or hours after transplantation
rapidly becomes cyanotic, mottled, and flaccid Ig and complement are deposited in the vessel wall, causing endothelial injury and fibrin-platelet thrombi neutrophils rapidly accumulate within arterioles, glomeruli, and peritubular capillaries fibrinoid necrosis occurs in arterial walls and then the kidney cortex undergoes outright necrosis (infarction) |
|
|
what is the treatment for hyperacute rejection of kidneys?
|
must be removed
|
|
|
what is acute rejection?
|
occurs within days of transplantation in untreated recipient or may appear months-years later
humoral type is associated with vasculitis cellular type is associated with interstitial mononuclear cell infiltrate |
|
|
what form of rejection is most commonly seen within the initial months after transplantation?
|
acute cellular rejection
|
|
|
describe acute cellular rejection
|
within initial months after transplantation
extensive interstitial mononuclear cell infiltration and edema as well as mild interstitial hemorrhage CD4+ and CD8+ T cells located in the glomerular and peritubular capillaries, as well as the tubules (causing focal tubular necrosis) in absence of accompanying humoral rejection, patients respond well to immunosuppressive therapy (cyclosporine) |
|
|
what is endothelitis?
|
injury to vascular endotheliall cells
|
|
|
describe acute humoral rejection
|
rejection vasculitis - manifested mainly by damage to blood vessels
marked thickening of the intima of the blood vessels with proliferating fibroblasts, myocytes, and foamy macrophages |
|
|
what is a strong indicator of humoral rejection?
|
deposition of the complement breakdown product C4d in the graft
|
|
|
how does chronic rejection of kidneys present clinically?
|
progressive renal failure manifested by a rise in serum creatinine over a 4-6 month period
|
|
|
what features dominate chronic rejection of kidneys?
|
vascular changes (dense, obliterative intimal fibrosis, principally in the cortical arteries), interstitial fibrosis, and tubular atrophy with loss of renal parenchyma
|
|
|
what is seen in glomeruli of kidneys being chronically rejected?
|
scarring, with duplication of basement membranes
"chronic transplant glomerulopathy" |
|
|
what cells are seen in chronically rejecting kidneys?
|
interstitial mononuclear cell infiltrates of plasma cells and numerous eosinophils
|
|
|
what is the usefulness of HLA matching in transplants?
|
in kidney transplants, there is substantial benefit if all of the polymorphic HLA alleles are matched (-A, -B, and -DR)
it is not even done in liver, heart, and lung transplants, because other considerations are more important |
|
|
what is the mainstay drug of immunosuppression in transplant recipients?
|
cyclosporine
|
|
|
how does cyclosporine work?
|
blocks activation of NFAT (nuclear factor of activated T cells; transcription factor)
NFAT usually initiates the transcription of cytokine genes (IL-2 particularly), but when blocked by cyclosporine, it is unable to |
|
|
how does azathioprine work as an immunosuppressant?
|
inhibits leukocyte development from bone marrow precursors
|
|
|
how do steroids work as immunosuppressants?
|
block inflammation
|
|
|
how does rapamycin work as an immunosuppressant?
|
inhibits lymphocyte proliferation
|
|
|
how does mycophenolate mofetil work as an immunosuppressant?
|
inhibits lymphocyte proliferation
|
|
|
what monoclonal anti-T-cell antibodies are used as immunosuppressants?
|
anti-CD3 (T cell coreceptor)
anti-CD25 (IL-2 receptor alpha chain) |
|
|
what are the benefits and costs of immunosuppression in transplant patients?
|
benefits - prolongs graft survival
costs - increases susceptibility to opportunistic infections |
|
|
why are liver transplants not HLA matched?
|
other factors are more important in determining whether the liver will be a good fit
rejection reaction is not as vigorous as might be expected from degree of HLA disparity |
|
|
where can hematopoietic stem cells be obtained?
|
bone marrow
peripheral blood after they are mobilized by administration of hematopoietic growth factors |
|
|
what two problems are unique to bone marrow transplantation?
|
graft-versus-host disease (GVH)
immunodeficiency |
|
|
when does GVH disease occur?
|
GVH = graft-versus-host
occurs any time immunologically competent cells or their precursors are transplanted into immunologically crippled recipients transferred cells recognize alloantigens in the host |
|
|
in what types of transplants can GVH disease occur?
|
GVH = graft-versus-host
most commonly in bone marrow solid organs rich in lymphoid cells (liver) transfusion of unirradiated blood |
|
|
what happens in GVH disease?
|
GVH = graft-versus-host
immunocompetent T cells present in the donor marrow recognize the recipient's HLA antigens as foreign and react against them |
|
|
how is GVH disease minimized in bone marrow transplants?
|
GVH = graft-versus-host
bone marrow transplants are done between donor and recipient that are HLA-matched using sensitive DNA sequencing methods for molecular typing of HLA alleles |
|
|
when does acute GVH disease occur?
|
GVH = graft-versus-host
within days to weeks after allogeneic bone marrow transplantation |
|
|
when does chronic GVH disease occur?
|
GVH = graft-versus-host
either following acute GVH or insidiously |
|
|
what are the major clinical manifestations of acute GVH disease?
|
GVH = graft-versus-host
immune system skin (generalized rash that may lead to desquamation in severe cases) liver (destruction of small bile ducts -> jaundice) intestines (mucosal ulceration -> bloody diarrhea) |
|
|
what are the major clinical manifestations of chronic GVH disease?
|
GVH = graft-versus-host
extensive cutaneous injury, with destruction of skin appendages and fibrosis of the dermis chronic liver disease (cholestatic jaundice) damage to GI tract (esophageal strictures) immune system devastation (involution of thymus, depletion of lymphocytes in lymph nodes) |
|
|
why are bone marrow transfusions not all merely depleted of T cells?
|
although this virtually eliminates GVH disease, the incidence of graft failures, EBV-related B-cell lymphoma, and recurrence of leukemia all increase
|
|
|
what is the graft-versus-leukemia effect?
|
bone marrow grafts (especially the immunocompetent T cells contained therein) are essential for eliminating recurrence of leukemia
if T cells are depleted from donor marrow, the recurrence of disease in leukemic patients is increased |
|
|
what factors cause immunodeficiency as a frequent complication of bone marrow transplantation?
|
1) prior treatment
2) myeloablative preparation for the graft 3) delay in repopulation of recipient's immune system 4) attach on host immune cells by grafted lymphocytes |
|
|
what infectious organism is particularly important in immunodeficiency secondary to bone marrow transplantation?
|
cytomegalovirus (CMV)
CMV-induced pneumonitis can be a fatal complication of bone marrow transplantation |
|
|
what are primary immunodeficiency disorders?
|
disorders of the immune system that are (almost always) genetically determined
|
|
|
what are secondary immunodeficiency disorders?
|
deficiency in the immune system as arises as a complication of cancers, infections, malnutrition, or side effects of immunosuppression, irradiation, or chemotherapy
|
|
|
when do most primary immunodeficiencies present? why?
|
between 6 months and 2 years of life
affected infants are susceptible to recurrent infections |
|
|
what is the characteristic immunodeficiency in X-linked agammaglobulinemia?
|
aka bruton's agammaglobulinemia
failure of B cell precursors (pro-B cells and pre-B cells) to develop into mature B cells |
|
|
describe the pathologic mechanism by which mature B cells aren't produced in X-linked agammaglobulinemia
|
aka bruton's agammaglobulinemia
Ig heavy-chain genes are rearranged first, in pre-B cells, and they are expressed on cell surface in association with a "surrogate" light chain, where they normally deliver signals that induce rearrangement of the light-chain genes Btk, the mutated tyrosine kinase, is necessary to transduce signals from the receptor, so when it is mutated the pre-B cell receptor cannot deliver signals and maturation stops at this stage |
|
|
what is the primary defect in X-linked agammaglobulinemia?
|
aka bruton's agammaglobulinemia
mutation in Bruton tyrosine kinase (Btk) gene, that renders its protein product unable to transduce signals from the pre-B cell receptor, stopping B cell maturation at the pre-B cells |
|
|
what is the inheritance pattern of Bruton's agammaglobulinemia?
|
aka X-linked agammaglobulinemia
X-linked inheritance pattern |
|
|
what is Btk?
|
Bruton tyrosine kinase
a tyrosine kinase that is associated with the Ig receptor complex of pre-B and mature B cells, that is needed to transduce signals from the receptor the gene (on the X chromosome) encoding Btk is mutated in the disease X-linked agammaglobulinemia (bruton's agammaglobulinemia) causing B cell maturation standstill at pre-B cells |
|
|
in what gender is Bruton's agammaglobulinemia seen?
|
aka X-linked agammaglobulinemia
X-linked disorder, so seen almost entirely in males only sporadic cases have been described in females |
|
|
when does X-linked agammaglobulinemia present? why?
|
aka bruton's agammaglobulinemia
about 6 month's of age maternal immunoglobulins are depleted |
|
|
what are the symptoms of X-linked agammaglobulinemia?
|
recurrent bacterial infections of the respiratory tract
- acute and chronic pharyngitis - sinusitis - otitis media - bronchitis - pneumonia |
|
|
what are the primary causative organisms of recurrent infections in patients with X-linked agammaglobulinemia?
|
aka bruton's agammaglobulinemia
Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus - organisms that are normally opsonized by antibodies and cleared by phagocytosis - |
|
|
what viral infections are patients with X-linked agammaglobulinemia especially prone to?
|
aka bruton's agammaglobulinemia
enterovirus infections (i.e. echovirus, poliovirus, coxsackievirus) |
|
|
what protozoan infections are patients with X-linked agammaglobulinemia especially prone to?
|
aka bruton's agammaglobulinemia
Giardia lamblia - normally resisted by secreted IgA - |
|
|
what are the characteristics of the classic form of X-linked agammaglobulinemia?
|
aka bruton's agammaglobulinemia
- B cells are absent or markedly decreased in circulation - serum levels of all classes of Igs are depressed - Pre-B cells are found in normal numbers in the bone marrow - germinal centers of lymph nodes, Peyer's patches, the appendix, and tonsils are underdeveloped - plasma cells are absent throughout the body - T cell-mediated reactions are normal |
|
|
what cell surface markers are present/absent on pre-B cells?
|
present: CD19 (B-lineage marker)
absent: B cell receptor (membrane Ig) |
|
|
what is the B lineage marker?
|
CD19
|
|
|
in what tissues are germinal centers found?
|
lymph nodes
Peyer's patches appendix tonsils |
|
|
what is the treatment for X-linked agammaglobulinemia?
|
aka bruton's agammaglobulinemia
replacement therapy with immunoglobulins (prophylactic IV Ig therapy allows most individuals to reach adulthood) |
|
|
what is the feature that is common to all of the disorders in the group titled "common variable immunodeficiency"?
|
hypogammaglobulinemia
usually serum levels of all antibody classes are low, but sometimes only IgG is affected |
|
|
what is common in the relatives of familial common variable immunodeficiency patients?
|
high incidence of selective IgA deficiency
|
|
|
what are the levels of B cells in common variable immunodeficiency?
|
normal or near-normal numbers in the blood and lymphoid tissues
|
|
|
what is the defect in common variable immunodeficiency?
|
inability of B cells, in blood and lymphoid tissues, to differentiate into plasma cells
could be caused by intrinsic B-cell defects or abnormalities in T helper cell mediated activation of B cells |
|
|
what are the clinical manifestations of common variable immunodeficiency?
|
recurrent sinopulmonary pyogenic infections
recurrent herpesvirus infections enterovirus infections (causing meningoencephalitis) Giardia lamblia infections |
|
|
what sex is affected by common variable immunodeficiency?
|
affects both sexes equally
|
|
|
when does common variable immunodeficiency present?
|
childhood/adolescence
later than X-linked agammaglobulinemia |
|
|
how does common variable immunodeficiency affect the B-cell areas of the lymphoid tissues?
|
B-cell areas of lymphoid tissues = lymphoid follicles in nodes, spleen, gut
hyperplastic B cells can proliferate in response to antigen but do not produce antibodies, and therefore the normal feedback inhibition by IgG is absent |
|
|
what immunoglobulin/antibody normally provides feedback inhibition to B cell proliferation?
|
IgG
|
|
|
what is the incidence of isolated IgA deficiency?
|
1 in 600 individuals of European descent in the US
far less common in blacks and Asians |
|
|
what is the basic defect in isolated IgA deficiency?
|
impaired differentiation of naive B lymphocytes to IgA-producing cells
|
|
|
what is the pathology of isolated IgA deficiency?
|
mucosal defenses are weakened
infections occur in the respiratory, GI, and urogenital tracts |
|
|
what is the major Ig in external secretions (mucosal defenses)?
|
IgA
|
|
|
what is the common presentation of symptomatic patients with isolated IgA deficiency?
|
recurrent sinopulmonary infections
recurrent diarrhea |
|
|
what antibodies are commonly deficient in isolated IgA deficiency, aside from IgA?
|
IgG2 and IgG4 subclasses of IgG
|
|
|
what reaction happens to some isolated IgA deficiency patients when they are infused with blood containing normal IgA?
|
severe, even fatal, anaphylactic reactions (because the IgA behaves like a foreign antigen)
|
|
|
what is hyper-IgM syndrome?
|
disorder in which patients can make IgM antibodies, but are deficient in their ability to produce IgG, IgA, and IgE antibodies
caused by a defect in the ability of helper T cells to deliver activating signas to B cells and macrophages |
|
|
what interaction is required for most functions of CD4+ helper T cells?
|
engagement of CD40 (on B cells, macrophages, and dendritic cells) by CD40L (on activated T cells)
- triggers Ig class switching and affinity maturation in B cells - stimulates the microbicidal functions of macrophages |
|
|
what are the two inheritance patterns of hyper-IgM syndrome?
|
X-linked inheritance (70% of patients) - mutations in gene encoding CD40L on Xq26
autosomal recessive inheritance (30% of patients) - mutations in gene encoding CD40 or gene encoding activation-induced deaminase |
|
|
what is activation-induced deaminase?
|
DNA-editing cytosine deaminase that is required for class switching and affinity maturation of B cells
|
|
|
what are the serum levels of antibodies in hyper-IgM syndrome?
|
elevated IgM
no IgA no IgE low IgG |
|
|
what are the serum levels of lymphocytes in hyper-IgM syndrome?
|
B cells - normal
T cells - normal |
|
|
what gives rise to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia in patients with hyper-IgM syndrome?
|
many of the IgM antibodies react with elements of blood
|
|
|
what is the clinical presentation of hyper-IgM syndrome?
|
recurrent pyogenic infections (level of IgG antibodies is low)
pneumocystis jiroveci-mediated pneumonia (only in CD40L mutations, b/c of defect in cell-mediated immunity) |
|
|
what is DiGeorge syndrome?
|
a T-cell deficiency that results from failure of development of the third and fourth pharyngeal pouches
leads to variable losses of T cell-mediated immunity, tetany, and congenital defects of the heart and great vessels abnormal appearance of mouth, ears, and facies |
|
|
what is derived from the fourth pharyngeal pouch?
|
thymus
parathyroids some of the clear cells of the thyroid ultimobranchial body |
|
|
what is the effect of DiGeorge syndrome on T cell zones of lymphoid organs?
|
T cell zones of lymphoid organs = paracortical areas of the lymph nodes and the periarteriolar sheaths of the spleen
they are depleted |
|
|
what is the inheritance pattern of DiGeorge syndrome?
|
DiGeorge syndrome is not a familial disorder
results from the deletion of a gene that maps to chromosome 22q11 |
|
|
what is severe combined immunodeficiency?
|
constellation of genetically distinct syndromes, all having in common defects in both humoral and cell-mediated immune responses
|
|
|
what is the clinical presentation of severe combined immunodeficiency?
|
prominent thrush (oral candidiasis)
extensive diaper rash failure to thrive morbilliform rash shortly after birth recurrent severe infections: - candida albicans - pneumocystis jiroveci - pseudomonas - cytomegalovirus - varicella - whole host of bacteria |
|
|
why do SCID patients get a morbilliform rash shortly after birth?
|
SCID = severe combined immunodeficiency
maternal T cells are transferred across the placenta and attack the fetus, causing GVH disease |
|
|
what is the most common form of SCID?
|
SCID = severe combined immunodeficiency
X-linked form resulting in a genetic mutation in the common gamma-chain subunit of cytokine receptors |
|
|
in what gender is SCID most common?
|
SCID = severe combined immunodeficiency
boys |
|
|
what cells are deficient in SCID?
|
mature T cells
NK cells B cells are normal in number, but Ab synthesis is impaired because of lack of T cell help |
|
|
what are the two inheritance patterns of SCID?
|
X-linked (more common) - mutation in common gamma-chain subunit of cytokine receptors
autosomal recessive - deficiency in adenosine deaminase (ADA) |
|
|
what is the autosomal recessive form of SCID?
|
genetic mutation causing deficiency of adenosine deaminase (ADA)
accumulation of deoxyadenosine and its derivatives (deoxy-ATP), which are toxic to rapidly dividing immature lymphocytes, especially those of the T-cell lineage |
|
|
what is bare lymphocyte syndrome?
|
disorder of deficiency of CD4+ T cells
caused by mutations that impair the expression of class II MHC (usually transcription factors that are required for class II MHC gene expression) considered a combined immunodeficiency because CD4+ cells are involved in cell-mediated immunity and in activating B cells (humoral immunity) |
|
|
what are the histologic findings in the most common forms of SCID?
|
thymus is small and devoid of lymphoid cells
in ADA SCID - remnants of Hassall's corpuscles can be found in X-linked SCID - thymus contains lobules of undifferentiated epithelial cells resembling fetal thymus |
|
|
what are Hassall's corpuscles?
|
structures found in the medulla of the human thymus, formed from eosinophilic dead type VI epithelial reticular cells arranged concentrically
|
|
|
what is Wiskott-Aldrich syndrome?
|
aka immunodeficiency with thrombocytopenia and eczema
X-linked recessive disease characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection, ending in early death |
|
|
what is the morphology of the thymus in Wiskott-Aldrich syndrome?
|
morphologically normal, at least early in the course of the disease
progressive secondary depletion of T lymphocytes in the peripheral blood and in the T-cell zones of the lymph nodes |
|
|
what are the T-cell zones of the lymph nodes?
|
paracortical areas
|
|
|
describe the antibody response of patients with Wiskott-Aldrich syndrome
|
do not make antibodies to polysaccharide antigens
poor response to protein antigens |
|
|
what are the serum Ig levels in Wiskott-Aldrich syndrome?
|
low IgM
normal IgG elevated IgA elevated IgE |
|
|
to what neoplasm are patients with Wiskott-Aldrich syndrome prone?
|
non-Hodgkin B-cell lymphomas
|
|
|
mutations of what gene cause Wiskott-Aldrich syndrome?
|
gene encoding Wiskott-Aldrich syndrome protein (WASP), located at Xp11.23
|
|
|
what is the function of WASP?
|
WASP = Wiskott-Aldrich syndrome protein
links membrane receptors, such as antigen receptors, to cytoskeletal elements may be involved in cytoskeleton-dependent responses, including cell migration and signal transduction essential functions of this protein in lymphocytes and platelets are unclear |
|
|
what is the treatment for Wiskott-Aldrich syndrome?
|
bone marrow transplantation
|
|
|
what is the most common genetic complement deficiency?
|
C2 deficiency
|
|
|
what is the manifestation of a deficiency of early components of the classical pathway of complement?
|
C1 (C1q, r, or s), C2, C4
no increased susceptibility to infections increased incidence of an SLE-like autoimmune disease |
|
|
what is the manifestation of a deficiency of components of the alternative pathway of complement?
|
properdin and factor D
recurrent pyogenic infections |
|
|
what is the manifestation of a C3 deficiency?
|
susceptibility to serious and recurrent pyogenic infections
increased incidence of immune complex-mediated glomerulonephritis |
|
|
what is the manifestation of a deficiency in components of the membrane attack complex?
|
C5, C6, C7, C8, C9
increased susceptibility to recurrent neisserial (gonococcal and meningococcal) infections |
|
|
what is caused by a deficiency in C1 inhibitor?
|
hereditary angioedema
|
|
|
what is hereditary angioedema?
|
autosomal dominant disorder that causes a deficiency of C1 inhibitor
Sx: - episodes of edema affecting skin and mucosal surfaces (larynx and GI tract) -> asphyxia -> nausea/vomiting -> diarrhea attacks happen after minor trauma or emotional stress |
|
|
what is C1 inhibitor?
|
component of complement
protease inhibitor whose target enzymes are C1r and C1s of the complement cascade, factor XII of the coagulation cascade, and the kallikrein system |
|
|
how are acute attacks of hereditary angioedema treated?
|
C1 inhibitor concentrates prepared from human plasma
|
|
|
what causes paroxysmal nocturnal hemoglobinuria?
|
deficiency of complement-regulatory proteins other than C1 inhibitor (DAF and CD59)
uncontrolled complement activation on the surface of red cells is the basis of hemolysis |
|
|
what is DAF?
|
decay-accelerating factor (aka CD55)
complement regulatory protein prevents the assembly of the C3bBb complex (the C3-convertase of the alternative pathway) or accelerates the disassembly of preformed convertase, thus blocking the formation of the membrane attack complex it is present on "self" cells to prevent complement from damaging them |
|
|
what is CD59?
|
aka protectin
complement regulatory protein inhibits the complement membrane attack complex by binding C5b678 and preventing C9 from binding and polymerizing it is present on "self" cells to prevent complement from damaging them |
|
|
what is caused by mutations in the complement regulatory protein, factor H?
|
underlie about 10% of cases of hemolytic uremic syndrome (renal disease)
characterized by microvascular thrombosis in kidneys |
|
|
what are the most common immunodeficiencies?
|
secondary immunodeficiencies are more common than disorders of primary genetic origin
most common secondary immunodeficiency is AIDS |
|
|
what is AIDS?
|
a disease caused by the retrovirus, human immunodeficiency virus (HIV), and characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations
|
|
|
what are the five groups of adults at risk for developing AIDS?
|
homosexual/bisexual men (50%)
IV drug abusers (20%) hemophiliacs (esp. those that received large amounts of factor VIII or factor IX concentrates before 1985; 0.5%) recipients of blood and blood components (non-hemophiliacs; 1%) heterosexual contacts of other high-risk groups (mainly IV drug users; 10%) |
|
|
what is the most rapidly growing group of AIDS-infected individuals?
|
heterosexual contacts of members of other high-risk groups (mainly IV drug users), especially women
|
|
|
what are the three major routes of transmission of AIDS?
|
sexual contact
parenteral inoculation passage of virus from infected mothers to newborns |
|
|
how is HIV transferred between homosexual men?
|
virus is carried in the semen, and it enters the recipient's body through abrasions in rectal or oral mucosa or by direct contact with mucosal lining cells
|
|
|
what are the two forms of HIV viral transmission between homosexual men?
|
direct inoculation into the blood vessels breached by trauma
infection of the dendritic cells or CCD4+ T cells in the mucosa |
|
|
how is HIV transmitted from a female to a male?
|
HIV is present in vaginal secretions and cervical cells of infected women
it enters the recipient's body through abrasions on the penis or in the oral mucosa or by direct contact with mucosal lining cells |
|
|
what is the effect of coexisting sexually transmitted diseases on HIV?
|
enhance all forms of sexual transmission of HIV, especially when the coexisting STD is associated with genital ulceration
|
|
|
in what three groups of individuals is HIV transmitted parenterally?
|
IV drug abusers
hemophiliacs who received factor VIII and factor IX concentrates random recipients of blood transfusion |
|
|
what is the major cause of pediatric AIDS?
|
mother-to-infant transmission via:
- transplacental spread in utero - infected birth canal in delivery - ingestion of breast milk |
|
|
how has mother-to-child transmission of AIDS been virtually eliminated in the US?
|
antiretroviral therapy given to infected pregnant women
|
|
|
describe HIV
|
human immunodeficiency virus
nontransforming human retrovirus member of the lentivirus family |
|
|
which genetic form of HIV is the most common type associated with AIDS in the US?
|
HIV-1 (also in Europe and central Africa)
HIV-2 is in West Africa and India |
|
|
what is the structure of the HIV-1 virion?
|
spherical
electron-dense, cone-shaped core surrounded by a lipid envelope derived from host cell membrane |
|
|
what is contained in the virus core of HIV-1 virions?
|
1) major capsid protein (p24)
2) nucleocapsid protein p7/p9 3) two copies of genomic RNA 4) three viral enzymes (protease, reverse transcriptase, integrase) |
|
|
what is the major capsid protein of HIV-1 virions?
|
p24
|
|
|
what are the three viral enzymes contained in the HIV-1 viral core?
|
protease
reverse transcriptase integrase |
|
|
what viral antigen is targeted by antibodies that are used for the diagnosis of HIV infection (via ELISA)
|
ELISA = enzyme-linked immunosorbent assay
p24 (the major capsid protein) is targeted - it is the most readily detected viral antigen |
|
|
what glycoproteins stud the viral envelope of HIV?
|
gp120
gp41 both are critical for HIV infection of cells |
|
|
what is the effect of anti-HIV-1 protease inhibitor drugs?
|
prevent viral assembly (of HIV) by inhibiting the formation of mature viral proteins
|
|
|
what are the three subgroups of HIV-1 (on the basis of genetic analysis)?
|
M (major; most common worldwide)
O (outlier) N (neither M nor O) |
|
|
what is the most common form (subtype of HIV) in the US?
|
HIV-1, subgroup M, subtype B
|
|
|
what are the two major targets of HIV infection?
|
immune system
central nervous system |
|
|
what is the hallmark of AIDS?
|
profound immunodeficiency, primarily affecting cell-mediated immunity
primarily the result of infection of and severe loss of CD4+ T cells, as well as impairment in the function of surviving T helper cells |
|
|
what cells of the immune system are infected by HIV?
|
macrophages
dendritic cells CD4+ T cells |
|
|
after HIV enters the body through mucosal tissues, what are the first cells infected?
|
T cells
dendritic cells macrophages |
|
|
what are the stages in the life cycle of HIV?
|
infection of cells
integration of the provirus into the host cell genome activation of viral replication production and release of infectious virus |
|
|
what molecule is used as a receptor for HIV to gain entry into cells? what are the coreceptor molecules?
|
CD4 is the main receptor
CCR5 and CXCR4 act as coreceptors |
|
|
what explains the selective tropism of HIV for CD4+ cells?
|
CD4+ cells = CD4+ T cells, monocytes/macrophages, and dendritic cells
requirement for CD4 binding to enter cells accounts for the selective tropism |
|
|
in addition to CD4, what must HIV virions bind to gain entry into a cell?
|
gp120 (on HIV envelope) must bind to CCR5 and CXCR4 (on the cell; macrophages, T helper cells, or dendritic cells) before the HIV virion can gain entry into the cell
|
|
|
how are HIV isolates distinguished based on their use of coreceptors?
|
R5 strains use CCR5 (M tropic)
X4 strains use CXCR4 (T tropic) R5X4 strains use both **binding is through gp120 on viral envelope** |
|
|
what is important about T-tropic HIV virus?
|
capable of infecting many T cells and even thymic T-cell precursors
cause greater T-cell depletion and impairment than M-tropic HIV |
|
|
what is the initial step in HIV infection of a cell?
|
binding of the gp120 envelope glycoprotein to CD4 molecules on the cell
- this binding leads to a conformational change that results in the formation of a new recognition site on gp120 for CCR5 or CXCR4 |
|
|
what leads to a conformational change in HIV envelope gp120 that results in the formation of a new recognition site on gp120 for CCR5 or CXCR4?
|
binding of gp120 to CD4 molecules
|
|
|
what causes the conformational change in HIV envelope gp41 that results in the exposure of the fusion peptide?
|
binding of gp120 to CCR5 or CXCR4
|
|
|
what is the fusion peptide?
|
the fusion peptide is a hydrophobic region at the tip of gp41 (a glycoprotein on the HIV viral envelope) that inserts into the cell membrane of target cells (T cells and macrophages) leading to fusion of the virus with the host cell
|
|
|
what happens after the fusion peptide inserts into the cell membrane of a target cell?
|
fusion of the virus with the host cell
virus core, containing the HIV genome, enters the cytoplasm of the cell |
|
|
polymorphism in what gene has been associated with different susceptibility to HIV infection?
|
gene encoding CCR5
about 1% of white Americans inherit two defective copies of CCR5 gene, and are rendered resistant to HIV infection and the development of AIDS associated with R5 HIV isolates heterozygotes for the defective CCR5 gene are not protected from AIDS, but the onset of their disease after infection is somewhat delayed |
|
|
list the steps of the infection portion of the HIV life cycle
|
viral gp120 binds to CD4 -> conformational change in gp120 (increases affinity for CCR5 and CXCR4) -> gp120/CD4 complex binds to CCR5 (or CXCR4) -> conformational change in gp41 (exposure of fusion peptide) -> gp41 membrane penetration ->membrane fusion -> entry of HIV dsRNA genome
|
|
|
what happens to the HIV viral RNA genome once it has entered a host cell?
|
undergoes reverse transcription via viral reverse transcriptase, leading to the synthesis of a double-stranded complimentary DNA (cDNA; aka proviral DNA)
|
|
|
what happens to HIV cDNA in quiescent T cells?
|
remains in the cytoplasm in a linear episomal form
|
|
|
what happens to HIV cDNA in dividing T cells?
|
it circularizes, enters the nucleus, and is integrated into the host genome
can then remain silent for months or years (latent infection) or can be transcribed with the formation of complete viral particles that bud from the cell membrane |
|
|
after HIV cDNA has integrated itself into the host cell genome, what happens?
|
can remain silent for months or years (latent infection)
OR can be transcribed with the formation of complete viral particles that bud from the cell membrane |
|
|
describe the steps of HIV viral replication
|
reverse transcriptase synthesizes proviral DNA (double-stranded, complimentary DNA) -> remains linear until cell is activated by cytokines -> activation of cell by cytokines -> proviral DNA circularizes -> enters the nucleus -> inserts into host cell genome -> replicated (proviral DNA transcribed to RNA and core structure built) by host cell machinery -> assembles in cytoplasm
|
|
|
in vivo, what types of T cells are infected?
|
memory T cells
activated T cells inefficient at productively infecting naive T cells |
|
|
why are naive T cells good at fighting of HIV infection?
|
they contain an active form of an enzyme that introduces mutations in the HIV genome
enzyme is APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3), a cytidine deaminase that introduces cytosine-to-uracil mutations in the viral DNA that is produced by reverse transcription |
|
|
in resting T cells, where is NF-kappaB?
|
sequestered in the cytoplasm in a complex with members of the IkappaB (inhibitor of kappaB) protein family
|
|
|
what happens to NFkappaB on T cell activation by antigen or cytokines?
|
cytoplasmic kinases that phosphorylate IkappaB (inhibitor of kappaB) target IkappaB for enzymatic degradation, thus releasing NF-kappaB and allowing it to translocate to the nucleus
in the nucleus, NF-kappaB binds to sequences within the promoter regions of several genes, including those of cytokines that are expressed in activated T cells |
|
|
how is the HIV DNA (after it's inserted into host genome) transcribed to form viral RNA transcripts?
|
the long-terminal-repeat sequences that flank the HIV genome contain NF-kappaB-binding sites that can be triggered by NF-kappaB
|
|
|
what is the result of completion of the HIV viral life cycle in most CD4+ T cells?
|
cell lysis
|
|
|
what protein binds NF-kappaB in the cytosol to inhibit the transcription factor activity of NF-kappaB?
|
IkappaB (inhibitor of kappaB)
**it is released when cytoplasmic kinases phosphorylate it and target it for enzymatic degradation** it = IkappaB |
|
|
approximately how many new viral HIV particles are produced every day?
|
100 billion
|
|
|
how many CD4+ T cells die every day in HIV-infected individuals?
|
1-2 billion
|
|
|
why does it seem, early in the course of an HIV infection, that the immunodeficiency caused by HIV is out of proportion to the level of infection?
|
many infected cells may be in mucosal and other peripheral lymphoid organs; death of these cells is a major cause of cell loss
to an extent, the immune system can replace dying T cells, hence the rate of T cell loss may appear deceptively low, but as the disease progresses renewal of CD4+ T cells cannot keep up with the loss of cells |
|
|
what are the mechanisms by which HIV directly kills infected cells?
|
increased plasma membrane permeability associated with budding of virus particles from infected cells
virus replication interfering with protein synthesis |
|
|
what are syncytia?
|
giant cells formed by the fusion of several cells
|
|
|
how are syncytia formed in HIV infection?
|
gp120 is expressed on productively infected cells, and it binds to CD4 molecules on uninfected T cells
this leads to cell fusion fused cells develop ballooning and usually die within a few hours |
|
|
what are the qualitative defects in T cells reported even in asymptomatic HIV-infected persons?
|
- reduction in antigen-induced T-cell proliferation
- decrease in TH1-type responses relative to the TH2 type - defects in intracellular signalling - selective loss of memory subset of CD4+ helper T cells early in the course of the disease |
|
|
even with potent antiviral therapy, which practically sterilizes the peripheral blood, latent HIV lurks where?
|
within CD4+ cells (both T cells and macrophages) in low-level chronic or latent infections
|
|
|
why are memory T cells particularly good persistent reservoirs for HIV?
|
they are long-lived, with a life span of months to years
|
|
|
what causes lymphopenia in HIV?
|
selective loss of CD4+ helper T cell subset
|
|
|
what are the abnormalities in AIDS associated with decreased T-cell function?
|
- preferential loss of activated and memory T cells
- decreased delayed-type hypersensitivity - susceptibility to opportunistin infections - susceptibility to neoplasms |
|
|
what are the abnormalities in AIDS associated with altered T cell function?
|
- decreased proliferative response to mitogens, alloantigens, and soluble antigens
- decreased cytotoxicity - decreased helper function for B-cell antibody production - decreased IL-2 and IFN-gamma production |
|
|
what are the abnormalities in AIDS associated with polyclonal B-cell activation?
|
hypergammaglobulinemia and circulating immune complexes
inability to mount de novo antibody response to new antigens poor responses to normal B-cell activation signals |
|
|
what are the abnormalities in AIDS associated with altered monocyte or macrophage functions?
|
decreased chemotaxis and phagocytosis
decreased class II HLA expression diminished capacity to present antigen to T cells |
|
|
how does the infection of macrophages compare to the infection of monocytes in HIV?
|
infection of macrophages may be high, while there are few infected monocytes in the blood
|
|
|
why can HIV-1 infect and multiply in terminally differentiated macrophages, though cell division is required for replication of most retroviruses?
|
HIV-1 vpr gene
Vpr protein allows nuclear targeting of HIV preintegration complex through the nuclear pore |
|
|
why do infected macrophages bud relatively small amounts of HIV virus from the cell surface, while CD4+ T cells are lysed?
|
even though they allow viral replication, macrophages are quite resistant to the cytopathic effects of HIV
maintain a large number of viral particles in cytoplasm while letting only a few bud out at a time |
|
|
what is the important site of viral replication in late stages of HIV, when CD4+ T cell numbers decline greatly?
|
infected macrophages
|
|
|
what are the functional defects seen even in uninfected monocytes in HIV-infected persons?
|
impaired microbicidal activity
decreased chemotaxis decreased IL-1 secretion inappropriate TNF secretion poor capacity to present antigens to T cells |
|
|
what is the role of mucosal dendritic cells in HIV?
|
they are infected by the virus and transport it to regional lymph nodes, where it is transferred to CD4+ T cells
|
|
|
how do dendritic cells promote infection of T cells with HIV?
|
express a lectin-like receptor that specifically binds HIV and displays it in an intact, infectious form to T cells
|
|
|
in HIV, what is the role of follicular dendritic cells in the germinal centers of lymph nodes?
|
similar to macrophages, they are potential reservoirs of HIV
|
|
|
what B cell-associated abnormalities are seen in patients with HIV?
|
- polyclonal activation
- germinal center B-cell hyperplasia (particularly early in the disease) - bone marrow plasmacytosis - hypergammaglobulinemia - formation of circulating immune complexes - inability to mount an antibody response to newly encountered antigens |
|
|
what factors in HIV infection can cause activation of B cells?
|
- reactivation or reinfection with CMV or EBV (both are polyclonal B cell activators)
- gp41 promotes B-cell growth and differentiation by itself - HIV-infected macrophages produce increased amounts of IL-6, which stimulates B-cell proliferation |
|
|
what are microglia?
|
cells in the CNS that belong to the macrophage lineage
|
|
|
what are the predominant cell types in the brain that are infected with HIV?
|
macrophages
microglia |
|
|
how is HIV carried into the brain?
|
infected monocytes
|
|
|
what causes the neurologic deficit in HIV/AIDS?
|
indirectly caused by viral products and by soluble factors produced by infected microglia (IL-1, TNF, IL-6)
|
|
|
what are the phases of pathogenetic events and clinical manifestations of HIV infection?
|
1) an acute retroviral syndrome
2) a middle, chronic phase (most pts. are asymptomatic) 3) clinical AIDS |
|
|
what are the characteristics of acute (early) HIV infection?
|
infection of memory CD4+ T cells in mucosal lympoid tissues
death of many infected cells few infected cells are detectable in the blood and other tissues |
|
|
what follows mucosal infection with HIV?
|
dissemination of the virus and the development of host immune responses
|
|
|
how long after HIV exposure can viral replication be detected in lymph nodes?
|
within days after the first exposure
|
|
|
when does an HIV-infected person seroconvert?
|
within 3-7 weeks of presumed exposure
|
|
|
what are the signs that an HIV-infected individual has mounted humoral and cell-mediated immune responses against the HIV?
|
seroconversion (3-7 weeks post-exposure)
development of virus-specific CD8+ cytotoxic T cells |
|
|
when are HIV-specific CD8+ T cells detected in the blood of an infected person?
|
about the time viral titers begin to fall (about 12 weeks)
|
|
|
what immune component that is the most likely responsible for the initial containment of HIV infection?
|
HIV-specific CD8+ T cells
there is a drop in viremia to low, but detectable levels by about 12 weeks after primary exposure |
|
|
what is the retroviral syndrome associated with HIV?
|
self-limited, acute illness with nonspecific symptoms (sore throat, myalgias, fever, weight loss, fatigue) resembling flulike symptoms
could also present with rash, cervical adenopathy, diarrhea, and vomiting typically occurs 3-6 weeks post infection and lasts for 2-4 weeks |
|
|
what is a useful surrogate marker of HIV disease progression?
|
extent of viremia, measured as HIV-1 RNA levels
useful in the management of people with HIV infection |
|
|
what are the three categories of HIV patients (based on CD4+ cell counts)?
|
greater than or equal to 500 cells/uL
200-499 cells/uL fewer than 200 cells/uL |
|
|
what are the most reliable short-term indicators of disease progression?
|
blood CD4+ T cell counts
|
|
|
what are the sites of continuous viral replication and cell destruction in chronic HIV infection?
|
lymph nodes
spleen |
|
|
what manifestations are present in the chronic phase of infection?
|
none to few
|
|
|
by what mechanisms does HIV escape immune control?
|
- destruction of the CD4+ T cells that are critical for effective immunity
- antigenic variation - down-modulation of class I MHC molecules |
|
|
what minor opportunistic infections develop during the chronic phase of HIV infection?
|
oral candidiasis
vaginal candidiasis herpes zoster mycobacterial tuberculosis autoimmune thrombocytopenia may also be noted |
|
|
what are the characteristics of AIDS?
|
- breakdown of host defense
- dramatic increase of plasma virus - severe, life-threatening clinical disease |
|
|
how does an AIDS patient present?
|
long-lasting fever (>1 month)
fatigue weight loss diarrhea serious opportunistic infections secondary neoplasms clinical neurologic disease |
|
|
without treatment, what is the normal chronic phase of an HIV patient, before it progresses to AIDS?
|
7-10 years
|
|
|
what are long-term nonprogressors?
|
untreated HIV-1-infected patients who remain asymptomatic for 10 years or more, with stable CD4+ T cell counts and low levels of plasma viremia (usually less than 500 viral RNA copies per mL)
consists of 5-15% of infected individuals |
|
|
what are elite controllers?
|
HIV-infected individuals that have undetectable plasma virus (50-75 RNA copies/mL)
consists of about 1% of infected individuals |
|
|
what accounts for the majority of deaths in untreated patients with AIDS?
|
opportunistic infections
many of which represent reactivation of latent infections, which are normally kept in check by a robust immune system but are not completely eradicated because the infectious agents have evolved to coexist with their hosts |
|
|
what are the most common pathogens in AIDS patients?
|
Pneumocystis jiroveci (pneumonia)
Candida CMV mycobacteria Cryptococcus neoformans Toxoplasma gondii Cryptosporidium herpes simplex virus papovaviruses Histoplasma capsulatum |
|
|
what is the most common fungal infection in patients with AIDS?
|
candidiasis
oral candidiasis is a sign of immunological decompensation, and it often heralds the transition to AIDS |
|
|
what infection often heralds the transition of patients to full-blown AIDS?
|
oral candidiasis
|
|
|
what are the presentations of CMV in AIDS patients?
|
disseminated disease
chorioretinitis (eye infection) esophagitis and colitis (GI infection) |
|
|
how does M. tuberculosis manifest in AIDS patients?
|
manifests early in the course of AIDS
pattern of expression depends on the degree of immunosuppression: - dissemination is more common in pts w/ very low CD4+ T-cell counts |
|
|
what is the major clinical manifestation of cryptococcosis in AIDS patients?
|
meningitis
|
|
|
what are the manifestations of Toxoplasma gondii in AIDS patients?
|
encephalitis
responsible for 50% of CNS mass lesions |
|
|
what is the manifestation of JC virus in AIDS patients?
|
JC virus is a human papovavirus
causes progressive multifocal leukoencephalopathy |
|
|
what is the manifestation of Herpes simplex virus in AIDS patients?
|
ulcerations involving mouth, esophagus, external genitalia, and perianal regions
|
|
|
what is the manifestation of protozoan infection (cryptosporidium, isospora belli, or microsporidia) in AIDS patients?
|
chronic, profuse, watery diarrhea with massive fluid loss
can also be caused by salmonella, shigella, and M. avium-intracellulare |
|
|
what tumors have increased incidence in AIDS patients?
|
kaposi sarcoma
non-Hodgkin B-cell lymphoma cervical cancer (women) anal cancer (men) |
|
|
what virus causes kaposi sarcoma?
|
kaposi sarcoma herpes virus (HHV8)
oncogenic DNA virus |
|
|
what virus causes B-cell lymphoma?
|
epstein barr virus (EBV)
oncogenic DNA virus |
|
|
what virus causes cervical and anal carcinoma?
|
human papillomavirus
oncogenic DNA virus |
|
|
what is the most common neoplasm in patients with AIDS?
|
Kaposi sarcoma
a vascular tumor that is otherwise rare in the US |
|
|
what are the characteristics of Kaposi sarcoma?
|
proliferation of spindle-shaped cells that express markers of both endothelial cells (vascular or lymphatic) and smooth muscle cells
profusion of slitlike vascular spaces, suggesting that the lesions may arise from primitive mesenchymal precursors of vascular channels |
|
|
what is the model of pathogenesis of Kaposi sarcoma?
|
spindle cells produce pro-inflammatory and angiogenic factors, which recruit the inflammatory and neovascular components of the lesion, and the latter components supply signals that aid in spindle cell survival or growth
|
|
|
to what type of cells is Kaposi sarcoma herpesvirus localized?
|
spindle cells
display predominantly latent infection |
|
|
what are the proteins produced in cells infected with Kaposi sarcoma herpesvirus that could stimulate spindle cell proliferation and prevent apoptosis?
|
viral homologue of cyclin D
several inhibitors of p53 |
|
|
what is Castleman disease?
|
a B-cell lymphoproliferative disorder in AIDS patients
linked to HHV8 |
|
|
what is body cavity-based primary effusion lymphoma?
|
rare B-cell lymphoma in AIDS patients
linked to HHV8 |
|
|
what are the three groups of AIDS-related lymphomas?
|
systemic
primary CNS body cavity-based |
|
|
describe systemic lymphomas in AIDS patients
|
involve lymph nodes as well as extranodal, visceral sites
constitute 80% of AIDS-related lymphomas CNS is most common extranodal site affected, then GI, then other locations |
|
|
describe body cavity lymphomas in AIDS patients
|
rare
unusual presentation as pleural, peritoneal, or pericardial effusions |
|
|
what virus latently infects half of the systemic and virtually all of the CNS lymphomas in AIDS patients?
|
epstein barr virus (EBV)
oncogenic DNA virus |
|
|
what is oral hairy leukoplakia?
|
white projections on the tongue, resulting from EBV-driven squamous cell proliferation of the oral mucosa
common in AIDS patients |
|
|
what are the neuropathologic changes associated with AIDS?
|
self-limited meningoencephalitis occuring at the time of seroconversion
aseptic meningitis vacuolar myelopathy peripheral neuropathies progressive encephalopathy (AIDS-dementia complex) |
|
|
what are the targets of antiretroviral drugs?
|
reverse transcriptase
viral protease viral integrase |
|
|
why are antiretroviral drugs given in combination?
|
to reduce emergence of mutants that develop resistance to any one
|
|
|
what is HAART?
|
highly active antiretroviral therapy
aka combination retroviral therapy name for treatment regimens for AIDS, that target viral reverse transcriptase, protease, and integrase usually combines at least three types of antiretroviral drugs |
|
|
what is the effect of a combination of at least three effective antiretroviral drugs and a motivated, adherent patient?
|
reduce HIV replication to below the level of quantification and remains there as long as the patient adheres to therapy
|
|
|
what is the drawback to people living longer with HIV?
|
they are not virus-free, so there is increased risk of spreading the infection
|
|
|
what can happen in patients with advanced HIV who are given antiretroviral therapy?
|
immune reconstitution inflammatory syndrome
a paradoxical clinical deterioration during the period of recovery of the immune system occurs despite increasing CD4+ T cells and decreasing viral load |
|
|
what are the long-term toxicities of HAART?
|
- lipoatrophy (loss of facial fat)
- lipoaccumulation (excess fat deposition centrally) - elevated lipids - insulin resistance - peripheral neuropathy - premature cardiovascular disease - kidney disease - hepatic dysfunction |
|
|
what is seen in biopsy specimens from enlarged lymph nodes in the early stages of HIV infection?
|
marked follicular hyperplasia
germinal centers seem to merge with the interfollicular area |
|
|
where is B cell hyperplasia noted in early stages of HIV infection?
|
lymph nodes (follicular hyperplasia)
bone marrow (increased plasma cells) peripheral blood (rouleaux, the abnormal stacking of red cells that results from hypergammaglobulinemia) |
|
|
what is the B cell pattern in late stages of HIV infection?
|
follicular involution (follicles are depleted of cells and organized network of follicular dendritic cells is disrupted)
"burnt-out" lymph nodes are atrophic and small and may harbor opportunistic pathogens later stages - spleen and thymus appear to be "wastelands" |
|
|
what is amyloid?
|
a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings
|
|
|
how does amyloid appear histologically?
|
amorphous, eosinophilic, hyaline, extracellular substance that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells
|
|
|
what is the effect of Congo red stain on amyloid?
|
under ordinary light - pink/red color to tissue deposits
with polarized light - green birefringence |
|
|
what is amyloidosis?
|
a group of diseases having in common the deposition of similar-appearing proteins
|
|
|
what makes up amyloid?
|
largely of continuous, nonbranching fibrils with a diameter of 7.5-10 nm
structure is identical in all types of amyloidosis |
|
|
what is the characteristic conformation of amyloid?
|
cross-beta-pleated sheet
|
|
|
what is responsible for the distinctive Congo red staining and birefringence of amyloid?
|
characteristic cross-beta-pleated sheet conformation
|
|
|
what are the three most common forms of amyloid proteins?
|
1) AL (amyloid light chain) - derived from Ig light chains produced in plasma cells
2) AA (amyloid-associated) - derived from a unique non-Ig protein synthesized by the liver 3) Abeta amyloid - synthesized from beta amyloid precursor protein |
|
|
what type of amyloid protein is found in the cerebral lesions of alzheimer disease?
|
Abeta amyloid
|
|
|
what is AL amyloid protein made from?
|
aka amyloid light chain
derived from Ig light chains produced in plasma cells |
|
|
what is AA amyloid protein made from?
|
aka amyloid-associated
derived from a unique non-Ig protein (SAA or serum amyloid A) synthesized by the liver |
|
|
what is Abeta amyloid protein made from?
|
beta amyloid precursor protein
found in alzheimer's plaques |
|
|
which form of Ig light chain composes most AL amyloid proteins analyzed?
|
lambda light chain
kappa chains have been IDed in some cases |
|
|
what is the deposition of AL amyloid associated with?
|
certain forms of plasma cell tumors
|
|
|
how are AA fibrils formed?
|
proteolysis of SAA (serum amyloid A), an acute-phase protein that is produced in the liver and circulates in association with HDLs
|
|
|
what is secondary amyloidosis?
|
amyloid deposits of AA amyloid (from SAA or serum amyloid A, the acute-phase protein)
secondary because it is associated with chronic inflammation |
|
|
how are Abeta fibrils formed?
|
derived from proteolysis of amyloid precursor protein, a large membrane glycoprotein
|
|
|
what is amyloid precursor protein?
|
an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons
primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export known as the precursor to beta-amyloid (Abeta) |
|
|
what is TTR?
|
transthyretin
a normal serum protein that binds and transports thyroxine and retinol |
|
|
what protein is deposited in familial amyloid polyneuropathies?
|
mutant form of TTR (and its fragments)
|
|
|
what protein is deposited in senile systemic amyloidosis?
|
TTR (normal amino acid sequence)
|
|
|
what protein is deposited in amyloidosis that complicates long-term hemodialysis?
|
beta2-microglobulin (forms Abeta2m amyloid fibril subunit)
component of MHC class I molecules, and a normal serum protein |
|
|
what protein is deposited in amyloidosis that complicates prion disease?
|
misfolded prion proteins aggregate in extracellular space and acquire structural and staining characteristics of amyloid protein
|
|
|
what are the minor components of amyloid?
|
serum amyloid P
proteoglycans highly sulfated glycosaminoglycans |
|
|
what is the function of serum amyloid P protein in amyloidosis?
|
contributes to amyloid deposition by stabilizing the fibrils and decreasing their clearance
|
|
|
from what does amyloidosis result?
|
abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function
|
|
|
why are diverse conditions associated with amyloidosis?
|
each condition results in excessive production of proteins that are prone to misfolding
|
|
|
how are misfolded proteins normally degraded?
|
intracellularly in proteasomes
extracellularly by macrophages |
|
|
how is SAA produced?
|
serum amyloid A
synthesized in liver cells under the influence of IL-6 and IL-1 |
|
|
what are the classifications of amyloidosis based on location?
|
systemic (generalized - involving several organ systems
localized - deposits are limited to a single organ |
|
|
what are the clinical subclassifications of amyloidosis?
|
primary amyloidosis (when associated with some immunocyte disorder)
secondary amyloidosis (when it occurs as a complication of an underlying chronic inflammatory or tissue-destructive process |
|
|
primary amyloidosis usually exhibits what type of amyloid?
|
AL type
systemic deposition |
|
|
what is the most common form of amyloidosis?
|
primary amyloidosis
|
|
|
what is multiple myeloma?
|
a plasma cell tumor charcterized by multiple osteolytic lesions throughout the skeletal system
|
|
|
what is referred to as Bence-Jones protein?
|
only the light chains of Ig molecules
presence of Bence-Jones proteins, though necessary, is by itself not enough to produce amyloidosis |
|
|
what are the amyloid deposits in reactive systemic amyloidosis?
|
systemic in distribution
composed of AA protein |
|
|
what conditions does reactive systemic amyloidosis commonly complicate?
|
rheumatoid arthritis
ankylosing spondylitis inflammatory bowel disease (crohn disease and ulcerative colitis) |
|
|
what is skin-popping? how does it produce amyloidosis?
|
injection of heroin subcutaneously
it is associated with chronic skin infections which seem to be responsible for the amyloidosis |
|
|
patients on long-term hemodialysis for renal failure develop amyloidosis as a result of deposition of what protein?
|
beta2-microglobulin
|
|
|
why is beta2-microglobulin accumulated in patients with long-term dialysis?
|
it is present in high concentrations in the serum of persons with renal disease
it is retained in the circulation because it cannot be filtered through dialysis membranes leads to amyloidosis |
|
|
what is the clinical manifestation of hemodialysis-associated amyloidosis?
|
carpal tunnel syndrome because of beta2-microglobulin deposition
amyloid deposits in the synovium, joints, or tendon sheaths |
|
|
what is the most common form of familial amyloidosis?
|
familial Mediterranean fever
autosomal recessive autoinflammatory condition associated with abnormally high production of IL-1 |
|
|
how is familial Mediterranean fever characterized clinically?
|
attacks of fever accompanied by inflammation of serosal surfaces (peritoneum, pleura, synovial membranes)
|
|
|
what is encoded by the gene for familial Mediterranean fever?
|
pyrin (a protein that regulates inflammatory reactions via the production of pro-inflammatory cytokines)
|
|
|
in what populations is familial Mediterranean fever found?
|
largely in individuals of Armenian, Sephardic Jewish, and Arabic origins
|
|
|
what makes up the amyloid fibril in familial Mediterranean fever?
|
AA proteins (derivative of serum amyloid A)
|
|
|
what is the inheritance pattern of familial Mediterranean fever?
|
autosomal recessive
|
|
|
what is the inheritance pattern of familial amyloidotic polyneuropathies?
|
autosomal dominant
|
|
|
what are familial amyloidotic polyneuropathies?
|
group of autosomal dominant disorders characterized by deposition of amyloid predominantly in peripheral and autonomic nerves
amyloid fibrils are made up of mutant TTRs |
|
|
where are nodular deposits of amyloid most often found?
|
lung
larynx skin urinary bladder tongue periorbital region |
|
|
where are endocrine amyloid deposits found?
|
- medullary carcinoma of the thyroid gland
- islet tumors of pancreas - pheochromocytomas - undifferentiated carcinomas of the stomach - islets of langerhans in patients with type II diabetes derived either from polypeptide hormones or unique proteins |
|
|
what is senile systemic amyloidosis?
|
systemic deposition of amyloid in elderly patients (70s and 80s)
called senile cardiac amyloidosis b/c of dominant involvement and related dysfunction of the heart (restrictive cardiomyopathy and arrhythmias composed of normal TTR molecules |
|
|
how do affected organs in amyloidosis look macroscopically?
|
- often enlarged and firm
- waxy appearance - if the deposits are large enough, painting the cut surface with iodine imparts a yellow color that is turned to blue after application of sulfuric acid |
|
|
what is the most common and potentially most serious form of organ involvement in amyloidosis?
|
amyloidosis of the kidney
|
|
|
where are nodular deposits of amyloid most often found?
|
lung
larynx skin urinary bladder tongue periorbital region |
|
|
where are endocrine amyloid deposits found?
|
- medullary carcinoma of the thyroid gland
- islet tumors of pancreas - pheochromocytomas - undifferentiated carcinomas of the stomach - islets of langerhans in patients with type II diabetes derived either from polypeptide hormones or unique proteins |
|
|
what is senile systemic amyloidosis?
|
systemic deposition of amyloid in elderly patients (70s and 80s)
called senile cardiac amyloidosis b/c of dominant involvement and related dysfunction of the heart (restrictive cardiomyopathy and arrhythmias composed of normal TTR molecules |
|
|
how do affected organs in amyloidosis look macroscopically?
|
- often enlarged and firm
- waxy appearance - if the deposits are large enough, painting the cut surface with iodine imparts a yellow color that is turned to blue after application of sulfuric acid |
|
|
what is the most common and potentially most serious form of organ involvement in amyloidosis?
|
amyloidosis of the kidney
|
|
|
how do amyloidotic kidneys appear on gross examination?
|
normal size and color, or in advanced cases may be shrunken due to ischemia produced by vascular narrowing induced by the deposition of amyloid within arterial and arteriolar walls
|
|
|
how do amyloidotic kidneys appear on gross examination?
|
normal size and color, or in advanced cases may be shrunken due to ischemia produced by vascular narrowing induced by the deposition of amyloid within arterial and arteriolar walls
|
|
|
how do amyloidotic kidneys appear on histologic examination?
|
deposits are primarily in glomeruli, but interstitial peritubular tissue, arteries,and arterioles are also affected
glomerular deposits first appear as subtle thickenings of the mesangial matrix, accompanied usually by uneven widening of the basement membranes of the glomerular capillaries capillary lumens are eventually obliterated and the obsolescent glomerulus is flooded by confluent masses or interlacing broad ribbons of amyloid |
|
|
how do amyloidotic kidneys appear on histologic examination?
|
deposits are primarily in glomeruli, but interstitial peritubular tissue, arteries,and arterioles are also affected
glomerular deposits first appear as subtle thickenings of the mesangial matrix, accompanied usually by uneven widening of the basement membranes of the glomerular capillaries capillary lumens are eventually obliterated and the obsolescent glomerulus is flooded by confluent masses or interlacing broad ribbons of amyloid |
|
|
how do amyloidotic kidneys appear on gross examination?
|
normal size and color, or in advanced cases may be shrunken due to ischemia produced by vascular narrowing induced by the deposition of amyloid within arterial and arteriolar walls
|
|
|
what are the two patterns of amyloidotic deposition in the spleen?
|
sago spleen
lardaceous spleen |
|
|
what are the two patterns of amyloidotic deposition in the spleen?
|
sago spleen
lardaceous spleen |
|
|
describe amyloidosis of the liver
|
amyloid appears first in the space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids
vascular involvement and deposits in Kupffer cells are frequent normal liver function is usually preserved despite sometimes quite severe hepatic involvement |
|
|
how do amyloidotic kidneys appear on histologic examination?
|
deposits are primarily in glomeruli, but interstitial peritubular tissue, arteries,and arterioles are also affected
glomerular deposits first appear as subtle thickenings of the mesangial matrix, accompanied usually by uneven widening of the basement membranes of the glomerular capillaries capillary lumens are eventually obliterated and the obsolescent glomerulus is flooded by confluent masses or interlacing broad ribbons of amyloid |
|
|
describe amyloidosis of the liver
|
amyloid appears first in the space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids
vascular involvement and deposits in Kupffer cells are frequent normal liver function is usually preserved despite sometimes quite severe hepatic involvement |
|
|
how do amyloidotic kidneys appear on gross examination?
|
normal size and color, or in advanced cases may be shrunken due to ischemia produced by vascular narrowing induced by the deposition of amyloid within arterial and arteriolar walls
|
|
|
what are the two patterns of amyloidotic deposition in the spleen?
|
sago spleen
lardaceous spleen |
|
|
how do amyloidotic kidneys appear on histologic examination?
|
deposits are primarily in glomeruli, but interstitial peritubular tissue, arteries,and arterioles are also affected
glomerular deposits first appear as subtle thickenings of the mesangial matrix, accompanied usually by uneven widening of the basement membranes of the glomerular capillaries capillary lumens are eventually obliterated and the obsolescent glomerulus is flooded by confluent masses or interlacing broad ribbons of amyloid |
|
|
describe amyloidosis of the heart
|
deposits begin as focal subendocardial accumulations and within the myocardium between the muscle fibers
expansion of myocardial deposits eventually causes pressure atrophy of myocardial fibers when amyloid deposits are subendocardial, the conduction system may be damaged |
|
|
describe amyloidosis of the liver
|
amyloid appears first in the space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids
vascular involvement and deposits in Kupffer cells are frequent normal liver function is usually preserved despite sometimes quite severe hepatic involvement |
|
|
describe amyloidosis of the heart
|
deposits begin as focal subendocardial accumulations and within the myocardium between the muscle fibers
expansion of myocardial deposits eventually causes pressure atrophy of myocardial fibers when amyloid deposits are subendocardial, the conduction system may be damaged |
|
|
how do amyloidotic kidneys appear on gross examination?
|
normal size and color, or in advanced cases may be shrunken due to ischemia produced by vascular narrowing induced by the deposition of amyloid within arterial and arteriolar walls
|
|
|
how do amyloidotic kidneys appear on histologic examination?
|
deposits are primarily in glomeruli, but interstitial peritubular tissue, arteries,and arterioles are also affected
glomerular deposits first appear as subtle thickenings of the mesangial matrix, accompanied usually by uneven widening of the basement membranes of the glomerular capillaries capillary lumens are eventually obliterated and the obsolescent glomerulus is flooded by confluent masses or interlacing broad ribbons of amyloid |
|
|
what are the two patterns of amyloidotic deposition in the spleen?
|
sago spleen
lardaceous spleen |
|
|
describe amyloidosis of the liver
|
amyloid appears first in the space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids
vascular involvement and deposits in Kupffer cells are frequent normal liver function is usually preserved despite sometimes quite severe hepatic involvement |
|
|
describe amyloidosis of the heart
|
deposits begin as focal subendocardial accumulations and within the myocardium between the muscle fibers
expansion of myocardial deposits eventually causes pressure atrophy of myocardial fibers when amyloid deposits are subendocardial, the conduction system may be damaged |
|
|
what are the clinical manifestations of amyloidosis?
|
at first, often entirely nonspecific (weakness, weight loss, light-headedness, sycope)
later more specific findings (relate to renal, cardiac, and GI involvement) |
|
|
what are the renal symptoms of amyloidosis?
|
proteinuria that may be severe enough to cause nephrotic sydrome
|
|
|
what is the presentation of cardiac amyloidosis?
|
insidious congestive heart failure, conduction disturbances, arrhythmias
|
|
|
what is the presentation of tongue amyloidosis?
|
causes enlargement and inelasticity to the point of hampering speech and swallowing
|
|
|
what is the presentation of stomach/intestinal amyloidosis?
|
malabsorption
diarrhea digestive disturbances |
|
|
on what is the diagnosis of amyloidosis dependent?
|
histologic demonstration of amyloid deposits in tissues
most commonly biopsied sites: - kidney (renal manifestations) - rectal tissues - gingival tissues |
|
|
what is the prognosis for individuals with generalized amyloidosis?
|
poor prognosis
|
|
|
what is the median survival of patients with immunocyte-derived amyloidosis?
|
2 years after diagnosis
persons with myeloma-associated amyloidosis have a poorer prognosis |
