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209 Cards in this Set
- Front
- Back
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Very high levels of TNF, which is produced in response to the bacteria.
Characterized by low blood pressure, disseminated intravascular coagulation, and metabolic disturbances. |
Septic Shock
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Natural killer cells are a class of lymphocytes that recognize infected and stressed cells and respond to killing these cells by secreting what cytokine?
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The macrophage-activating cytokine IFN gamma
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Cytokines involved in Inflammasome
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IL-1β and IL-18
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binds to peptidoglycans of Gram -positive bacteria ,
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TLR 2
Surface TLRs |
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binds to LPS of Gram -negative bacteria,
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TLR 4
Surface TLRs |
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binds to flagellin of various bacteri
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TLR 5
Surface TLRs |
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binds to ds-RNA
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TLR 3
Endosomal TLRs |
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binds to ss- viral RNA
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TLR 7 and TLR 8
Endosomal TLRs |
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binds to bacterial unmethylated cpg DNA and viral DNA
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TLR 9
Endosomal TLRs |
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binds to peptidoglycans from Gram-negative bacteria.
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NOD1
Cytoplasmic sensors: |
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binds to peptidoglycans from Gram-positive bacteria
Cytoplasmic sensors |
NOD 2
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binds to HCV RNA
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Viral (Rig Like Receptors,RIG):
Cytoplasmic sensors |
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Activation of what receptor forms the multicomplex form of Inflammasome?
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NLR
(Nod-like receptors) |
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Type of Immunity:
Always present No memory Encoded in germline Limited diversity Intact host cells not recognized |
Innate Immunity
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Type of immunity:
Stimulated by microbes Memory Somatic recombination of gene segments greater diversity can react against the host |
Adaptive Immunity
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Type of Adaptive immunity that deals with extracellular microbes in circulation or vesicles. B cells recognize PCLAN (proteins, carbohydrates, lipids, antigens, nucleic acids)
Antibodies |
Humoral Immunity
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Type of adaptive immunity that deals with intracellular microbes in cytoplasm. T cells: CD4 and CD8 help macrophages kill microbes and kill infected cells respectively. T regulatory cells suppress immune response
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Cell-mediated immunity
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host playing active response resulting in memory (caused by natural infection or vaccine)
Specificity and memory are both present |
Active immunity
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conferred by adoptive transfer to recipient with no protection. obtained from another host (maternal to fetus), only lasts for weeks for months. B cells go away. Specificity is present, but not Memory
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Passive Immunity
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microbial molecules that are the targets of innate immunity. receptors of innate immunity that recognize these structures are called
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Pathogen associated molecular patterns (PAMPS)
pattern recognition receptors (PRR) |
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Molecules that are released form stressed or necrotic cells.
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Damage-associated molecular patterns
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Hypothesis that predicted that clones of lymphocytes specific for different antigens arise before encounter with these antigens, and each antigen elicits an immune response by selecting and activating the lymphocytes of a specific clone.
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The clonal selection hypothesis
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PRRs recognize structures that are characteristic of microbial pathogens/altered self and are not present on mammalian cells.expressed by macrophages, monocytes, dendritic cells, neutrophils, B cells and epithelial cells.
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PRR (Pattern recognition receptor)
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Examples of antigen presenting cells (APCs)
Capture of antigens to display for lymphocytes |
dendritic and macrophages, follicular dendritic cells
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Antigen receptors of most T cells only recognize peptide fragments of protein antigens that are bound to specialized peptide display molecules called:
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MHC molecules which are on the surface of specialized cells called Antigen presenting cells.
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Name of different types of macrophages in different tissues
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Microglia (CNS), Kupffer (Liver)
Alveolar macrophage (Lungs) Osteoclasts (bone) |
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Common portals of entry for microbes:
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Skin, Gastrointestinal tract, and Respiratory Tract
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Resides in the germinal centers of lymphoid follicles in the peripheral lymphoid organs and displays antigens that stimulate the differentiation of B cells in the follicles. DO NOT present antigens to T cells, but to B cells
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Follicular dendritic cell
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Granulocytic effector immune cells- Four types
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Neutrophils, Eosinophils, Basophils, Mast cells
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The most abundant circulating white blood cell –also called polymorphonuclear leukocyte (PMN)- First cells to arrive at the site of Inflammation
Do not act as antigen presenting cells Deficiency- (neutropenia) causes severe bacterial infections Deficient in neutrophil function: causes chronic granulomatous disease |
Neutrophil
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Kill antibody coated parasites by exocytosis (e.g helminths)
Large pink crystal granules Heightened number in inflammatory infiltrates such as bronchial infections and asthma |
Eosinophils
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Bilobed nucleus, large blue granules, Non-phagocytic ,
In circulation , structural and functional similarities to mast cells Express high-affinity Fc receptors for IgE , Release active substances during allergic and hypersensitivity reactions |
Basophils
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Formed in the tissue from bone marrow precursor cells
Have granules with preformed mediators released after stimulation (histamine, prostaglandins and leukotrienes) Stimulation occurs by the anaphylotoxins or by cross-linking of surface IgE Major effector cell of allergic and hypersensitivity reactions |
Mast Cells
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Sites of Lymphocyte maturation
(Bone Marrow ,Thymus) lymphocytes first express antigen receptors and attain maturity and clones develop |
generative lymphoid organs
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Sites of Lymphocyte activation
(LN, Spleen lymphoid tissues) naive lymphocytes are activated by antigen to become effector cells to initiate induction of adaptive immunity |
peripheral lymphoid organs
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When bone marrow is damaged hematopoiesis may occur at non-bone marrow sites
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liver and spleen
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Thymocytes whose receptors bind with low avidity to self peptide-self MHC complexes are stimulated to survive
Thymocytes that do not recognize self MHC are permitted to die |
Positive selection:
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is the process in which thymocytes whose receptors bind strongly to self peptide-self MHC complexes are deleted
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Negative selection:
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there is congenital absence of thymus - born with severe deficiency of T-cell mediated immunity
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DiGeorge syndrome
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T lymphocytes are concentrated outside, but adjacent to the follicles, contains dendritic cells that present antigens to T lymphocytes.
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paracortex.
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B cells are concentrated in these discrete structures, located around the periphery or cortex of each node. If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central region called a germinal center. Follicles contain FDCs that are involved in the activation of B cells.
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follicles
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in the spleen T cells are concentrated in:
in the spleen B cells reside in |
periarteriolar lymphoid sheaths (PALS)
Follicles |
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Naive T cells / Dendritic cells express _____ receptor for chemokine (in T cell zone)
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CCR7
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Naive B cells express _____ receptor for chemokine (in follicles/ B cell Zone
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CXCR5
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Naive B and T cells enter the node through artery through specialized vessels called
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high endothelial venules (HEV) in the cortex.
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major site of phagocytosis of antibody-coated microbes
Serving as filter of the blood for blood-borne antigens Red pulp macrophages remove the microbes and dying red blood cells from blood |
Spleen
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Two anatomically defined mucosal lymphoid tissues
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Peyer's patches and pharyngeal tonsils
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Dermis T cells comprise of both
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CD4+ /CD8+ cells and dermal dendritic cells
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Intraepidermal T cells comprise of
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CD8+ cells (2%)
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Peyer's patches are in lamina propria of small intestine -like lymph nodes - B cells (70%),T cells(10-30%,CD8+T), M cells
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GALT
Persistent HIV has reservoirs in the GALT |
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Mucosal surfaces of genitourinary, gastrointestinal tract and respiratory tracts are colonized by lymphocytes and dendritic cells that initiate responses to foreign antigens
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MALT
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Bronchus associated lymphoid tissue comprises of
Pharyngeal tonsils ( are lymphoid follicles like Peyer's patches) |
BALT
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Cell Surface CD antigens
Helper T cells |
CD4, CD3, CD28, CD40 L
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Cell Surface CD antigens
Cytotoxic T cells |
CD8 , CD3
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Cell Surface CD antigens
B Cells |
MHC class II ,IgM, B7, CD19, CD20, CD21(receptor for EBV), CD40
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Cell Surface CD antigens
Macrophages/Dendritic cells |
MHC class II, B7, CD14 (LPS receptor), CD40 (binds to CD40L on T cells), Have Receptors for Fc and C3b
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Cell Surface CD antigens
NK cells |
Receptors for MHC class I, CD16 (binds Fc for IgG), CD56
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All nucleated cells
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(except mature red cells) have MHC class I
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Class II MHC restricted T cells, thymocyte subsets, monocytes, macrophages.
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CD4
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T cells, thymocytes
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CD3
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Class I MHC restricted T cells, thymocyte subsets.
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CD8
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Cytokine that is produced by Phagocytes and dendritic cells. Induce increased IFN-γ production by NK and T cells
Eradicate intracellular microbes by promoting T helper cells and increase cytolytic activity |
IL-12
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Produced mainly by activated macrophages and regulatory T cells
Is an Anti-inflammatory cytokine Inhibits IL-12 production by activated macrophages and dendritic cells and also Inhibits co stimulatory molecule and class II MHC molecules on these cells. |
IL-10
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Produced by macrophages , endothelial cells, some T cells.
Induces Liver : Synthesize Acute Phase proteins Induces proliferation of plasma B cells Regulates balance of IL-17 producing Th17 and T reg cells Il-6 together with TGF-b stimulates naïve T cells differentiation to Th-17 On the other hand, IL-6 inhibits Treg differentiation induced by TGF-b Anti IL-6 Receptor biologic effective to treat autoimmune diseases. |
IL-6
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Increases expression class I MHC : on infected cells and enhances killing by cytotoxic T Lymphocytes and NK cells
Inhibits viral replication |
Type I interferons for intracellular viral infections
IFN-α Produced by viral infected cells and by mononuclear phagocytes. (IFN-β – is produced by fibroblasts). Pegylated interferon-alpha along with anti-viral therapy for treating hepatitis C infection. |
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First cytokine to be produced by CD4 T cells.Stimulates survival and proliferation of T cells. Also known as T cell growth factor.
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IL-2
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Produced by Th-2 cells and inhibits Th-1 cells B cell isotype switching to IgE.
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IL-4
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Produced by Th-2 and mast cells B cell Ig switch to IgE.
Activator of eosinophils in helminthic infections. |
IL-5
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Produced by Th-2 and mast cells. B cell Ig switch to IgE. Increases epithelial mucus production by cells.
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IL-13
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Produced by Th-1 cells. Potent activator of macrophages. Stimulates the production of antibody isotypes that promote the phagocytosis of microbes. stimulates the expression of class II MHC molecules and B7 costimulators on macrophages and dendritic cells,
Induces Th-1 and inhibits Th-2 cell production, NOTE: “Induces B cell isotype switch to complement-fixing IgG subclasses”. Principal macrophage activating (increases MHC I and MHC II on APCs ) |
IFN-gamma (adaptive immunity functions)
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Secreted by Th-17 cells
Induced by IL-6+ TGF beta . Increase chemokine and cytokine production by cells. Activates neutrophils , promotes inflammation. |
IL-17
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immunosuppressor for T cells and APCs , IMP: Induces B cell Ig switch to IgA, Differentiation of Th17 and Treg, also induces tissue repair ,collagen synthesis
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TGF-β
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CD4 Helper T cell subsets:
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Th1 Th2 Th17, Regulatory T cells, Follicular Helper T cell
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Transcription factors for TH-1, TH-2, TH-17
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Th-1: T-bet
Th-2: GATA-3 Th-17: RORyT |
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Th-17 differenitation is triggered by TGF-beta, in the presence of these inflammatory cytokines, which are produced by APCs
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IL-6
IL-1 IL-23 Produced by macrophages and dendritic cells. |
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Type of lymphocytes that are activated by antigen and costimulators that differentiate into CTLs (effector cells) that are able to kill infected cells expressing the antigen.
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CD8 T lymphocytes
Effector CTLs kill infected cells by secreting proteins that create pores in the membranes of the infected cells and induce DNA fragmentation and apoptotic death of these cells. |
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CD4 T cell subset Follicular Helper T cell that secretes this cytokine
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IL-21 cytokine -class switching affinity maturation of
Memory B cells |
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Immunosuppressive cytokines by Regulatory T cells
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IL-10 & TGF-β
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are substances that react specifically with an antibody or T cell receptor.
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Antigens
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Any substance that enhances the effects of a drug or increases the immunogenicity of an antigen.
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Adjuvants
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Small organic molecules with antigenic binding properties, but are not immunogenic (capable of independently initiating an immune response
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Haptens
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Ability of a substance (immunogen) to induce a humoral or cell-mediated immune response.
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Immunogenicity
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differ in amino acid sequence between antibodies of different antigen binding specificities) are depicted as VL (on light chains) or VH (on heavy chains).
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Variable domains
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binds to Fc receptors on B cells and other antigen presenting cells and activates intracellular signaling cascades.
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Fc region
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region produced by papain cleavage that contains one antigen-binding arm.
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Fab region
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cleaves immunoglobulins at the hinge region leaving an Fc containing portion and an F(ab’)2 antigen binding portion that has both antigen binding arms.
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Pepsin
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determined by heavy chain constant region (antibody class and function)
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Isotype
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determined by heavy chain and light chain variable regions (antigen binding specificity)
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Idiotype
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determined by allelic polymorphisms
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Allotype
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Antibodies bind to specific antigenic sites called
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epitopes
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The binding affinity (strength of binding) is influenced by ________ in the variable domains of the antibody.
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complimentary determining regions (CDRs)
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What immunoglobulin is produced by plasma cells of the lamina propria in GI and respiratory tracts that is actively transported through mucosal epithelial cells?
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IgA
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What properties are usually seen in B cell antibody secondary responses?
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Class switching and affinity maturation
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When the gene segments are spliced together there is diversity at the splice site so that a large number of different antibody rearrangements are made from a limited set of combinations. This is accomplished by removal or addition of nucleotides at the ends of the gene segments where they are spliced together.
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junctional diversity
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different combinations of V, D, J, & C segments
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combinatorial diversity
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Surface IgM or IgD cross-linking with antigen initiates intracellular signaling that leads to B cell activation and differentiation into plasma cells or memory B cells
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B Cell Antigen Receptor Signaling
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the only Ig transmitted across placenta, it is the only Ig that binds macrophage and neutrophil Fc receptors. is the most prominent serum Ig, and it has longest half-life (~3 weeks).
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IgG
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a given V gene can combine with numerous D and J regions as depicted in the following illustrations. In light chain recombinations V genes are joined directly to J genes
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Gene rearrangement (recombination)
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Mostly during secondary B cell responses the immunoglobulin locus will undergo further recombination to produce antibodies of the same specificity but different isotypes.
This only occurs in the presence of helper T cell secreted cytokines and T cell cross-signaling with B cells. Different cytokines will elicit switches to different classes. |
XI. Antibody Isotype Switching
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During the life of a mature B cell, the rearranged immunoglobulin genes accumulate mutations in the variable regions of the heavy and light chain genes resulting in yet another mechanism for the generation of diversity in binding specificity and affinity. This process is referred to as
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somatic hypermutation.
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B cells producing higher affinity antibodies are provided survival advantages and thus secondary and subsequent B cell immune responses generate higher and higher affinity antibodies. This process is called
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affinity maturation
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Drugs with the suffix “zumab”
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humanized monoclonal antibodies
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Drugs with the suffix “ximab”
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human/murine chimeric monoclonal antibodies
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Drugs with the suffix “mumab”
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fully human monoclonal antibodies
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Drugs with the suffix “omab” or “onab”
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murine monoclonal antibodies
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detect and quantify specific proteins in cell lysates or fluids using antibodies as probes.
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Western Blotting
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A primary antibody (usually monoclonal) is bound to the surface of a 96 well plate and test samples containing antigen of unknown concentration are added along with antigen of known doses to generate a standard curve. Amount of antigen capable of binding to the antibody is proportional to the antigen concentration. The plate is washed and a secondary antibody labeled with an enzyme is allowed to bind to the antigen. Substrate is added and a color or fluorescent reaction is measured using a plate reader. Sensitive method of determining antigen concentrations (as low as 1 pg/ml). Commonly used to measure cytokine or growth factor levels in serum or other fluids.
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ELISA
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Cell surface antigens or intracellular antigens are labeled with monoclonal antibodies (mAbs) that are tagged with fluorochromes. Cells that bear the antibodies are detected using
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Flow Cytometry
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When the antibody titer gets elevated, microbes covered with antibodies bind to B cell Fc receptors which inhibit the response of cross-linked Ig receptors.
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Inhibition of B Cell Responses
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A test that relies on agglutination of particulate antigen or antigen on a cell surface and soluble antibody. Anti-human immunoglobulin (Coombs reagent) is used to promote crosslinking of antibodies and antigens which causes agglutination.
Important clinical applications include: Typing of Rh determinants on RBCs, detection of anti-Rh antibodies in the serum of Rh- women, and diagnosis of Autoimmune Hemolytic Anemia. |
Coombs test
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States that in order for productive T cell activation to occur, two separate types of signals must be received; one from the TCR and a second from co-stimulatory molecules. The co-stimulatory signals are only present in sufficient quantity during an infection or time of “danger”. If only the TCR signal is received by the cell (in the absence of infection) then anergy or cell death will occur. This is a mechanism by which T cells that react with self antigens and damage uninfected tissues are controlled.
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Two signal hypothesis:
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a state of unresponsiveness to subsequent activation stimuli (a mechanism of peripheral tolerance to self antigens or non-dangerous antigens.
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Anergy
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Interactions between antigen presenting cells (APCs) and T cells are complex and involve numerous adhesion molecules (some listed on the previous two slides) as well as costimulatory molecules. After antigen recognition by the TCR these molecules arrange themselves into a supramolecular structure called the
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immunologic synapse or supramolecular activation cluster (SMAC).
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Two distinct mechanisms of CTL killing
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Release of granzymes into the cell. Pokes hole in cells and granzymes go in.
Fas binding activates cascades that lead to apoptosis |
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Effector T Cell Migration
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Endothelium near infection sites express selectins and ICAM-1 and VCAM-1 that enable effector T cell binding and entry into tissue.
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These cytokines promote inflammation in a variety of ways which include induction of adhesion molecules on the surface of leukocytes and endothelium, activation of PMNs and other leukocytes, and production of other cytokines
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, IL-1, IL-6, IL-12, IFN-g and TNFa
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Vasoactive amine
released by mast cells is an example. It causes vasodilation, vascular permeability, and release of arachidonic acid. |
Histamine
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Surface molecules found on leukocytes and endothelium that bind to carbohydrates. These molecules allow for loose binding that slows leukocytes and facilitates the initial rolling of lymphocytes along the cell walls of blood vessels.
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Selectins
P-selectins are found on platelets and endothelium. E-selectins are found on endothelium and activated T cells. L-selectins are found on leukocytes |
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Receptors present on the surface of leukocytes that enable firm adhesion to endothelium via binding to adhesion molecules
found on the surface of the endothelial cells. |
ICAM-1 and VCAM-1
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The b2 integrins LFA-1 on the surface of lymphocytes and MAC-1 on macrophages
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facilitate ICAM-1 binding and are critical for trafficking of these cell types.
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Lack of b2 integrins results in a severe immunodeficiency known as
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(Leukocyte Adhesion Deficiency).
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A similar disease called LAD II is caused by a deficiency in
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Sialyl-Lewis factor which is the receptor for E-selectin and P-selectin.
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Inhibit cyclooxygenases (COX-1,2 or both) and therefore inhibit production of prostaglandins, thromboxanes, and prostacyclins.
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Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
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Inhibitors of both COX-1 and COX-2:
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Aspirin, Ibuprofen, Naproxen
AIN |
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Inhibitor of COX-1
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Indomethacin
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Inhibitors of COX-2
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Celecoxib (Celebrex), Rofacoxib (Vioxx)
CV |
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released from membrane phospholipids by the enzymes PLA2, PLC, and PLD initiates a cascades that results in the production of several potent inflammatory mediators.
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arachidonic acid (AA)
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produce leukotrienes, protaglandins, thromboxanes, and prostacylins which are potent inflammatory mediators
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arachidonic acid (AA)
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Leukotriene Pathway Inhibitors
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LTRAs (Leukotriene Receptor Antagonists): block leukotriene functions (example: bronchoconstriction)
montelukast (Singulair)- asthma, allergic rhinitis zafirlukast (Accolate) - asthma 5-lipoxygenase Antagonist: block leukotriene production zileuton (Zyflo) - asthma |
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Inhibit PLA2 and therefore inhibits AA metabolism. Also inhibit T cell proliferation and cause T cell apoptosis.
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Corticosteroids: Hydrocortisone, dexamethasone, prednisone, etc.:
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receptors are in airway mucous, gastric parietal cells and in the vascular and central nervous
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H2 receptors
Antihistamines target histamine receptors and inhibit histamine binding. |
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found in the smooth muscle of the intestines, bronchi, and blood vessels.
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H1 receptors
Antihistamines target histamine receptors and inhibit histamine binding. |
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recombinant IL-1Ra; blocks IL-1 binding, RA treatment
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Kineret
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fusion protein that binds TNF receptors and blocks TNFa and TNFb binding, RA treatment
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Etanercept (Enbrel):
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anti-TNFa antibody that blocks TNFa binding, RA treatment
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Infliximab (Remicade):
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Selective Adhesion-Molecule (SAM) Inhibitors
humanized monoclonal antibody against VLA-4 (integrin-a4) which is present on leukocytes and mediates binding to VCAM-1 on inflamed endothelium and other receptors necessary for leukocyte migration. – used in treatment of MS and Chrohn’s |
Natalizumab (Tysabri):
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General immunosuppressant; inhibits DNA synthesis and therefore inhibits cell growth.
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Methotrexate
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helpful in the differential diagnosis of patients with autoimmune or connective tissue disorders.
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Detection and identification of antinuclear antibodies (ANA)
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Factors Which May Give Rise To A Positive ANA Result
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Malignancies of Various Types
Various Infectious Diseases Age Pregnancy Circulating Immune Complex Disease States Various Medications (>20 known; antiarrhythmics, antihypertensives, antipsychotics, antibiotics, etc; hydralazine and procainamide are best known) |
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functional activation of T lymphocytes that occurs when these cells recognize antigens without adequate levels of the costimulators (second signals) that are needed for a full T cell activation.
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Anergy
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immunological tolerance to different self antigens in the gernative lymphoid organs
Negative selection in T lymphocytes is a mechanism |
Central Tolerance
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Mature T cells recognize self antigens leads to inactivation, apoptosis, or self reactive lymphocytes are suppressed by Regulatory T cells
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Peripheral Tolerance
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How do infections promote autoimmunity
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Bystander activation: APCs are activated by microbes causing tolerance breakdown
Molecular mimicry: microbe contains antigens that cross-react or mimic self antigens |
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Regulatory T cells require these to suppress the activation of self-reactive lymphocytes and maintain homeostasis and tolerance
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IL-2 and the transcription factor FoxP3
Mutation can cause deficiency of Reg T cells |
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criteria of classification: 4 or more of 11 criteria symptoms.
system vasculitis High titered ANA: Elisa Test Antinflammatory treament: Anti IL-6 with what drug? |
SLE HLA DR2, DR3
Actemra |
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inflammatory disease involving joints
Rheumatoid factors which is antibody to the Fc portion of the host IgG. Generally of Ig M class Antibodies to CCP Decrease complement levels in synovial fluid, contains high TNF, IL-1, IL-8, with what treatment drug? |
RA, HLA-DR4
Entercept, anti-TNF |
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Autoimmune Disease
Ocular, oral dryness caused by lymphocyte and plasma cell infiltration of the lacrimal and salivary glands Anti-SSA ENA |
Sjorgren's Syndrome
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Autoimmune Disease
ANA with speckled or nuclear pattern Anticentromere antibodies in patients with crest syndrome Raynaud's phenomenon |
Systemic Sclerosis/Scleroderma
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Autoimmune Disease
lymphocytotic and plasma cell infliltration of involved skin and or muscle. AA: anti-Jo-1, anti-SRP, anti-Mi-2 |
Myositis: Polymyositis, Dermamyositis
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Autoimmune disease
chronic atrophic gastritis, failure of production of intrinsic factor due to blocking by antibody to prevent binding to vitamin B12. Type 1: blocking Type 2: binding Parietal cell antibody found |
Pernicious Anemia
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Autoimmune disease
anti-islet antibodies close association of hla antigens dr3 and dr4 insulin autoantibodies |
DM type 1 dr3,dr4
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autoimmune disease
inflammatory destruction and obliteration of intrahepatic bile ducts, followed by development of cirrhosis and liver failure antimitochondrial antibodies sp100 antibodies |
Primary Biliary Cirrhosis
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Autoimmune disease
Villous atrophy and malabsorption. Hypersensitivity to grain marker antibodies are IgA anti-tissue transglutimanse Associated with wheat gluten, gliadin |
Celiac Disease/Gluten-Sensitve Enteropathy DQ2, DQ8
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Autoimmune disease:
chronic disease resulting from an immune-mediated destruction of hepatic tissues Type I: ANA, SMA autoantibodies present Type 2: LKM antibodies |
Autoimmune Hepatits HLA DR3, DR4
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Autoimmune disease
weakness of striated muscle due to impaired neuromuscular transmission, reduction in number of Ach receptors. Achr blocking autoanitbodies present in 50% Achr modulating autoantibodies in 90% |
Myasthenia Gravis
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Autoimmune Disease
demyelinating disorder of CNS, mediated by autoreactive T cells Increase CSF IgG, presence of oligoclonal bands Increased production of INF gamma and TNF in blood Increase in IL-12 and expression of CCR5, CXCR3 on T cells. |
Multiple Sclerosis
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autoimmune disease
AA stimulate growth and division of thyroid cells reactive to thyroglobulin and thyroid microsmal antigen circulating lymphocytes which are sensitized to thyroid antigens |
Hashimoto's thyroiditis: antibodies to thyroglobulin
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Autoimmune disease
antibody to TSH receptor anti-thyrogllobulin anti-microsomal/thyroid peroxidase |
Grave's Disease
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Autoimmune Disease
inflitration of the thyroid with lymphocytes AA present Anti-thyroglobulin (90%) Anti-microsomal/thyroid peroxidase Block growth and metabolism |
Primary Hypothyroidism/Myxedema
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autoimmune
AA against antigens (desmoglein) in the intercellular zones of the epidermis Ig and complement deposited in intercellular matrix of patient's skin |
Pemphigus HLA DR4
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Autoimmune disease
A on skin basement membrane Ig and complement are deposited in dermoepthitelial junction of affect skin in a linear pattern |
Bullous Pemphigoid
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Autoimmune disease
diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis. production of AA reactive with glomerular and alveolar basement membranes Ab are type II or cytotoxic type Linear deposition of IgG and complement on basement membranes |
Goodpature's syndrome
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Autoimmune disease
deposition of Ig and complement in the glomeruli circulating immune complexes Exogenous or foreign antigens Endogenous or self antigens |
Immune complex nephritis Type III
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Autoimmune disease
group A streptococcal infection inflammation of several organs (heart, brain, joints) antibodies to streptococcal cellular (M protein) Susceptibility associated with HLA DR 4,2,1,3,7 |
Heart Rheumatic Fever- post infection
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Autoimmune
acclerated immunolgic mediated destruction of erythrocytes warm autoimmune hemolytic anemia, Positive Coombs test, IgG against RBC Cold autoimmune hemolytic anemia: IgM against RBC |
Immune Mediate Anemia-tYPE ii
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Transfusion reactions, ABO incompatible RBC. Naturally occurring IgM anti or anti B ab bind to the incompatible RBC and activate resulting hemolysis
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Autoimmunity Hemolytic ANemia: transfusion reactions
part of Immune Mediate Anemia |
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Maternal IgG ab cross the placenta and bind to fetal RBC resulting in hemolysis. RhD negtive women carrying a RHd positive baby.
Erythroblastosis fetalis: development of anti-D IgG |
Hemolytic Disease of the Newborn
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transplantation of stem cells (hematopoietic) or tissue or an organ from a donor to a recipient/host
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Engraftment
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Transplantation using blood
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Transfusion
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Transplant, located in same individual
same Ag Accepted |
Autograft
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Transplant, genetically identical individuals (identical twins)
Ag identical Accepted |
Isograft
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Transplant, different individuals of the same species
Ag different Rejected |
Allograft
(MHC alloantigens are typed for matching in clinical) |
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Transplant, individuals of different species.
Different Ag Rejected |
Xenograft
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reaction of preformed anti-ABO antibodies in the reciepent with ABO antigens on the surface of endothelium of the graft (thrombosis, necrosis of vessel wall)
Happens within minutes of engraftment |
Hyper-acute Graft Rejection
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occurs in 11-14 days
called primary (first-set) rejection mediated by CD8+ T cells reactive to alloantigens on the graft endothelial cells and parenchymal cells. Alloreactive antibodies may also contribute to vascular injury Similar to Type IV Hypersensitivity Reaction. Direct allorecognition by donor APC |
Acute Rejection
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occurs months to years after the engraftment
Chronic DTH reaction in vessel wall (arteriosclerosis of vascular endothelium) leading to luminal occulsion. Causes intimal smooth muscle cell proliferation. Cause unclear |
Chronic Rejection
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The mainstay of preventing and treating rejection of organ transplants is ________ (before and after transplant) designed maintly to inhbit T cell activation and its effector functions
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Immunosuppresion for Allograft Rejection
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Recipient's T cell recognizes unprocessed allogenic MHC molecule on graft APCs. T cell binds directly to an intact allgoneic MHC molecule on a graft APC in Acute Rejection
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T cell Direct Allorecognition (of unprocessed allogenic MHC peptide)
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Allogenic MHC molecules from graft cells are taken up and processed by recipient's APCs. Peptide fragments of MHC molecules are bound and presented by recipient (self) MHC molecules. T cell recognizes processed peptide of allogenic MC molecule bound to self MHC molecule on host APC.
Chronic Rejection |
T cell indirect allorecognition (recipients's APC process allogenic MHC peptide bound on to self MHC)
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Donor-Recipient Matching for Successful Transplantation
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ABO blood grouping: agglutination (hyperacute rejection)
Crossmatching (Cytotoxic antibody assay) for preformed antibodes in recipients. (Hyperacute or Acute vascular rejection) Tissue Typing (Serology/PCR): HLA matching on B cells expressing booth classes as target cells in the test. Mixed Lymphocyte Reaction: DNA synthesis test for alloreactive T cells of BM donor checked by mixing donor and recipient lymphocytes. Test performed before bone marrow transplantation |
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T lymphocytes in bone marrow graft respond to host alloantigens to produces:
Caused by reaction of grafted mature T cells in the marrow inoculum with alloantigens of the immunocomprised host. Reaction against MH antigens of the host. Careful HLA matching is required. |
Graft Versus Host Disease (GVHD)
Bone Marrow Rejection |
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Type of GVHD where there is epithelial cell death (in skin, GI, respiratory tract) takes 7-10 days is fatal
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Acute GVHD
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Type of GVHD where there is fibrosis and atrophy of one for more organs: complete dysfunction of affected organ- takes 100 days to 5 years: MAY BE FATAL
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Chronic GVHD
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Antigens that are expressed on tumor cells but not on normal cells are called tumor specific antigens
Are unique to individual tumors/or shared by same type of tumors Generate immune responses leading to tumor rejection |
Tumor Specific antigens
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Tumor antigens that are also expressed on normal cells
Result of aberrant expression or normal gene dysregulation |
Tumor associated antigens
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Expressed at high levels in cancer cells and in normal developing fetal tissues
Carcinoembryonic antigen( CEA ,CD66e) present on fetal ( gut , pancreas and liver) or embryonic cells but disappear in adult normal cells Elevated levels in sera of colon, breast, pancreas and stomach cancer Alpha-fetoprotein (AFP) present in fetal liver and yolk sac Serum AFP elevated in Hepatocellular carcinoma and some gastric , pancreatic and testicular tumors |
Oncofetal antigens
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Kill infected tumor cells with reduced class I MHC (inhibitory signals not engaged in NK cells)
Target IgG antibody -coated tumor cells by Fc receptors on NK cells (CD16)-mediated ADCC killing |
Innate Immune Responses to Tumors
By NK cells |
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In vitro demonstration of killing tumor cells vs. normal cells efficiently
Mechanism not known ? direct recognition of surface antigens Macrophages induce IFN –γ production by tumor-specific T cells IFN –γ production increase Lysosomal enzymes/ Nitric oxide production by macrophages Macrophages Induce TNFα production that results in thrombosis of tumor blood vessels |
Innate Immune Responses to Tumors
By Macrophages and Dendritic cells : |
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T Lymphocytes: CD8+ cytotoxic T lymphocytes (CTL effective in anti-tumor immunity in vitro (observed in animal experiments)
-CD4+ helper T cells – their role is less clear -May provide cytokines for effective CTL development (TNFα, IFN-γ) Increase tumor class I MHC expression -IFN –γ may activate macrophages – to kill tumors B lymphocytes: Serum antibodies to tumor antigens may kill tumors – by activating complement or by ADCC by NK cells e.g. Antibodies against EBV or HPV encoded antigens to these viral tumors |
Adaptive Immune Responses to tumors
T cell and B responses seem to occur |
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Tumor vaccines : involve stimulation with killed tumor cells or tumor antigens
Administration of tumors modified to express high levels of co-stimulatory molecules Systemic cytokine therapy: Stimulating T cell proliferation DNA vaccines Viral vectors |
Active Immunotherapy
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Adoptive cellular therapy (tumor reactive T or NK cells)
Anti-tumor antibody therapy : antibody coupled to bacterial immunotoxins for efficient complement activation |
Passive Immunotherapy
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Systemic cytokine therapy for tumors
Cytokines that are involved: |
IL-2 and interferon-alfa 2b are two cytokines approved by the FDA for treatment of cancer. IL-2 has demonstrated activity against renal cell, melanoma, lymphoma, and leukemia. Interferon has activity in the same histologies but also in Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia.
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Lymphocytes from blood or tumor infiltrate-expanded in culture by IL-2
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Adoptive cellular therapy-
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Tumor Immunodiagnosis
Detection of tumor cells and their products |
Myeloma proteins (blood or urine)(Multiple Myeloma)
Alpha- feto protein, AFP (Liver cancer, Hepatitis) Carcinoembryonic antigens,CEA (GI cancers) Prostate –specific antigens- for early detection of prostate cancer |
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C3 convertase C3bBb
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Alternative Pathway
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C3 convertase C4b2a
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Classical Pathway
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C1 is multi subunit (C1q,C1r and C1s) consists of six identical subunits with central core with arms-H , binds to Fc region of IgG and IgM antibody that have interacted with antigen. ( Type III Hypersensitivety)
C1 binding does not occur to antibodies that have not complexed with antigen |
Classical Pathway: C1 binding to Fc portion of IgM and IgG
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Activated in the absence of antibody by the attachment of plasma mannose binding lectin (MBL) to microbes
MBL is structurally similar to a component of C1 of classical pathway and serves to activate C4 MBL after binding mannose rich glycans, associates with MASP-1,MASP-2 (MBL serine proteases-similar to C1r and C1s) in normal serum to cleave C4 and C2 forming C3 convertase (C4b2a) Rest of pathway same as classical pathway in formation of C5 convertase |
The Lectin Pathway : C3 convertase C4b2a
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Late steps of Complement activation
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C5 Convertase C3bBbC3b and C4b2aC3b: Assembly of MAC involves polymerization to form membrane pore on microbial surface or infected or tumor cell.
5 a is Potent Anaphylactic Chemotactic : activates PMN mast cells |
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Regulators of complement activation:
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C1-INH in plasma
DAF on epithelial cells inhibits C3 convertase action |
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C1 INH deficiency causes -
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hereditary angioneurotic edema
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Deficiency of C3
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Repeated pyogenic infections
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Complement proteins : primarily produced by ________ although monocytes,
macrophages and epithelial cells can also produce important amounts. |
hepatocytes
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The smaller cleavage products C3a, C4a, C5a, called _______
What do they attract? |
anaphylatoxins
Apart from attracting phagocytes, they cause mast cell degranulation and enhance vessel permeability Thus facilitating access of plasma proteins and leukocytes to the site of infection |
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Cell bound C3b is an opsonin
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promotes phagocytosis of coated cells
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Deficiencies of complement proteins and disease
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Classical Pathway
C1NH : Hereditary angioedema -overproduction of C2b C1,C2,C4:Predisposition to SLE - Failure to clear Immune complexes in the tissues Lectin Pathway : MBL :Suceptibility to bacterial infections in infants who have inability to initiate lectin pathway Alternative Pathway : Factors B or D : Suceptibility to pus forming bacterial infections - lack of sufficient opsonization of the bacteria |
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Component C3 : Immunodeficiency more severe and is usually fatal in early life
Factor H or I : - causes C3 deficiency and susceptibility to bacterial infections |
Deficiency of DAF and CD59 : on erythrocytes causes paroxysmal nocturnal hemoglobinuria - inherited deficiency –patients need repeated blood transfusions
C9 and MAC formation deficiency : Lack of terminal components C5 - C9 causes repeated Neisseria infection Impaired bactericidal activity |
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Immunosuppressed or Immunodeficient patient immunized with live viral vaccine
Immune serum globulin administrated Pregnancy Prior allergic reaction to vaccine Acute febrile illness |
Contraindication to Vaccination
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Have highly resistant outer coats (e.g. M leprae) __________ blocks the ability of macrophages to respond to the activation effects of gamma IFN . Infected cells may loose their efficiency as antigen presenting cells ,Several organisms (e.g. Mycobacterium) can escape from the phagosome to multiply in the cytoplasm. The organism (e.g. M. tuberculosis) may ultimately kill the phagocyte.
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Mycobacterium
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