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111 Cards in this Set

  • Front
  • Back
Components of innate immunity
epithelial barriers, phagocytes, NK cells, complement
Receptors on phagocytes that recognize pathogens
Mannose residues, n-formyl methionine, and Toll
Effect of TLR activation
Activation of NF-kB, stimulation of microbicidal activities of phagocytes
Complement pathways of innate immunity
Alternative and lectin (the classical pathway is used by adaptive immunity)
Circulating proteins of innate immunity
Mannose-binding lectin, c-reactive protein, elements of lung surfactant
Microbial products that stimulate TLRs
LPS (Gram -), flagellin, bacterial peptidoglycan (Gram +), HSP 60, unmethylated bacterial DNA, double stranded RNA (list on pg 195)
60%-70% of lymphocytes in the blood
Mature naive T cells
Do gamma-delta T cells require APCs?
Nope
NKT cells recognize what?
Glycolipids displayed by MHC-like molecule CD1
Accessory molecules on T cells (in addition to signal transducers CD3 and that squiggle)
CD4, CD8, CD2, CD28 and integrins CD4 and CD8 distinguish between helper and cytotoxic T cells, respectively
CD4 T cells recognize which MHC molecules? CD8?
Class II. Class I.
What two signals do T cells require to be activated?
First, an antigen presented by the correct MHC molecule to the CD4/CD8 complex, then the CD28 molecule on the T cell must bind to CD80 and CD86 on the APC
Proliferative cytokine of T cells
IL-2
Cytokines:
TH1 Cells, purpose?
TH2 Cells, purpose?
TH1: IL-2, Interferon-Gamma: delayed hypersensitivity, macrophage activation, synthesis of opsonins and complement-fixing antibodies
TH2: IL-4, IL-5, IL-13: synthesis of non-antibody fixing antibodies, like IgE, and activating eosinophils
What are Igalpha/Igbeta and CD3, respectively?
The signal transducing molecules of B cell receptors and T cell receptors
Other nonpolymorphic B cell proteins that are necessary for their function
Complement receptors, Fc receptors, CD21 and CD40
How do helper T cells activate B cells
Engaging CD40 ( a TNF receptor family member) . This is essential for B cells to mature, produce IgG/A/E
Mutation in the CD40L on T cells
X-linked hyper-IgM syndrome
Two types of dendritic cells
Interdigitating dendritic cells (aka dendritic cells) and follicular dendritic cells (in spleen and lymph nodes)
Three useful attributes of interdigitating (APC) dendritic cells
1. Location: under epithelium
2. Expression of innate receptors: TLR and mannose
3. When bound to antigen, they chemotax their little butts to T cell regions of lymphoid organs
4. Present MHC II and costimulatory molecules to communicate with CD4 T cells
Helpful characteristics of follicular (nonmotile) dendritic cells
1. Fc receptors for IgG and C3b, hence can recognize Ab-Ag and complement complexes
2. Present to B cells
3. But . . . active in promoting AIDS
NK cell targets and why we care
Viral-infected cells, tumor cells, and normal pathogenically activated cells: they do not require activation in the classic sense
Why don't NK cells kill everything in sight?
They have a MHC I inhibitory molecule, and since MHC I is expressed on all body cells, they are usually inhibited
What two factors contribute to the NK cell activity in the innate immune system?
1. Loss of inhibitory MHC I molecules in infected cells
2. "Activation" by stress-induced proteins or viral proteins interacting with NKG2D
Cytokines that mediate communication between leukocytes
Interleukins (The IL)
Cytokines that mediate innate immunity
IL-1, TNF, Interferons in class 1, IL-6 (IL-12 and Interferon-gamma do both innate and adaptive)
Cytokines that regulate lymphocyte growth/activation/differentiation
IL-2: T cell growth factor
IL-4: Diff. to TH2, B cell diff
IL-12: Diff to TH1
IL-15: Growth of NK cells
TGF-B/IL-10: Downregulate
Cytokines that activate inflammatory cells
IFN-gamma: macrophage activator
IL-5: activates eosinophils
TNF: This should be familiar
Cytokines that regulate lymphocyte movement
Chemokines (usually C-C and C-X-C)
-Macrophages make C-X-C
-T cells makes C-C
Properties of cytokines
1. Produced by several
2. Pleiotropic
3. Autocrine/Paracrine/Endocrine
4. High-affinity binding
Where is the major histocompatibility complex?
Chromosome 6
Three types of MHC - I molecules? Molecular structure?
Where expressed?
What for?
HLA-A,HLA-B, HLA-C: three domain alpha chain attached to a little beta2 microglobulin, expressed on every cell, present antigens to CD8 cells (Figure 6-10). They present viral (intracellular) proteins
Three types of MHC - II molecules?
Molecule structure?
Where expressed?
What for?
HLA-DP, HLA-DQ, HLA-DR: noncovalent alpha and beta chain, each with two domains; expressed on APCs. They present exogenous peptides first digested in the endosome or lysosome to CD4 cells
What's the purpose of the MHC?
T cell selection and effect immune responses to body invaders, for good or for ill (allergies result when an MHC-II presents a harmless antigen to the T cells, like ragweed)
Diseases associated with the HLA locus?
1. Inflammatory disease: ankylosing spondylitis, all associated with HLA-B27
2. Inborn errors of metabolism: hereditary hemochromatosis
3. Autoimmune disease: mainly the DR locus
4 main disorders of the immune system
1. Hypersensitivity rxn
2. Autoimmune diseases
3. Immunodeficiencies
4. Amyloidosis
In two or three words, characterize each of the 4 hypersensitivity rxns
1. immediate/Anaphylaxis
2. Antibodies:Hemolytic anemia
3. Ag-Ab with complement deposition: SLE
4. T-cell mediated: MS, atopic dermatitis
Immediate and late responses of Type I rxns
Immediate: Vascular leak, vasodilation, spasm or gland secretion
Late: lymphocyte infiltrate and mucosal destruction
Key cell of Type I rxns
Mast cells, stimulated by the anaphylatoxins and IgE Fc receptors
Signature cytokines of the Th2 cells that turn on IgE-producing B cells in Type I rxns
IL-4, IL-5, IL-13
Cytokine that activates eosinophils
IL-5
Why do Type I hypersensitivities appear to worsen with subsequent exposure?
The leftover IgE antibodies will crosslink and speed up mast cell degranulation as well as de novo synthesis.
Mediators of Type I rxns
Histamine, Acid hydrolases/proteases, heparin/chondroitin, leukotrienes, prostaglandins, PAF and of course a thousand cytokines
Susceptibility to Type I rxns
Genetically determined: hence the idea of atopy. You are born with atopy.
Systemic Type I? Local Type I?
Anaphylaxis: edema, shock, difficulty breathing.
Atopic allergy: dermatitis, pollen allergy, etc.
Three different antibody-dependent mechanisms of Type II hypersensitivity rxns?
1. Opsonization->phagocytosis: destruction in transfusions, example
2. Complement and Fc: glomerulonephritis in organ grafts
3. Antibody dysfunction (stimulation and inhibition): hyperthyroidism and myasthenia gravis
What two types of antigens cause Type III rxns and injury (via Ab-Ag deposition)
1. Exogenous: anything foreign
2. Endogenous: commonly against tissues, sometimes against blood
Classic disease examples of Type III rxns
Serum sickness (injecting humans with horse serum), SLE, Acute glomerulonephritis, reactive arthritis
What two factors affect the manifestation of Type III illnesses?
1. Size of the complexes (small is bad)
2. Dysfunction or overload of the mononuclear phagocyte system
Morphological consequences of Type III illnesses, typically
1. Neutrophil/Monocyte overload in area
2. Vasodilation and edema via kinin activation
3. Necrosis and fibrous accumulation
What is the Arhus rxn, or local immune complex disease?
Acute tissue necrosis from Type III vasculitis, appears 4-10 hours later
Example of Type IV rxns?
Type I Diabetes, MS, rheumatoid arthritis
Two forms of Type IV hypersensitivity
1. Delayed type: TH1 i.e. tuberculin rxn. If infected, a cuff will occur at inoculation site. Often causes granuloma formation. Big cytokines are IL-12, IFN-gamma, TNF
2. Cytotoxicity: CD8 cells get activated, kill via perforins and Fas-Fas induced apoptosis
Two pathways via which recipient's T cells reject transplants
Direct and indirect antigen recognition
Direct pathway of transplant rejection
T cells in recipient see allogenic MHCs on APCs in graft (APCs express both class I and II). Both CD4 and CD8 activate via their respective class MHC. CTLs kill cells with perforins and Fas-Fas, CD4 become TH1 and promote inflammation. Why, if there are no antigens on the foreign MHCs? Unknown. Very important in acute rejection
Indirect pathway of transplant rejection
The recipient APCs process foreign antigens from the graft, present them to the recipient CD4 cells, which then enter the graft and all hell breaks loose. Very important in chronic rejection.
Antibody pathway of transplant rejection - two forms
1. Hyperacute: the antibodies to the donor are already in the recipient (i.e. a second blood transfusion from a similar source), usually causing immediate lesions and infarct in graft vasculature
2. Acute: Slower, manufacture of new antibodies that still attack the vasculature: rejection vasculitis
Cyclosporine
Nephrotoxic immunosuppressant
Major morphological changes in chronic rejection
Intimal fibrosis, glomerular loss: slow kidney failure, in other words.
Graft versus host disease:
Immunocompetent cells are transplanted into an immunocompromised recipient, and attack them
Central tolerance versus peripheral tolerance
The death of self-reactive T and B cells during their maturations results in central tolerance. Should self-reactives live, they are inactivated via anergy/suppression/death from apoptosis/antigen sequestration=peripheral tolerance.
AIRE gene failure
Autoimmune polyendocrinopathy (tolerance failure)
What is the true cause of autoimmune disorders, since there are so many ways to mediate tolerance?
Susceptibility genes, which cause a failure in tolerance somewhere along the line, often in the face of infection/inflammation (when the immune system in normally stimulated)
Role of infection in promoting autoimmunity
1. Infection upregulates costimulators, failure of clonal anergy
2. Infectious agents may have similar peptide sequences to body antigens, causing a subsequent autoimmunity: rheumatic heart dsease after strep infection.
Epitope spreading
An initial autoimmune response exposes new epitopes on antigens, promoting additional rxns.
SLE:
Multi-autoimmunity due to failure in self-tolerance, particularly DNA/histones/RNA/nucleolus, causing injury to skin, joints, kidney, serosa. Chart on 228.
Predominant antibody in SLE
Anti-double stranded DNA, anti-small ribonuclear proteins
Predominant antibody in systemic sclerosis
Anti-DNA topoisomerase I
Predominant antibody in scleroderma
Anti-centromeres
Predominant antibody in Sjorgen syndrome
Anti-ribonuclear proteins
Hypersensitivity in SLE
Type III complex deposition causes lesions. The guilty antibody is IgG.
Like most autoimmune disorders, progression of the disease in SLE . . .
. . . has radical but morphologically clear effects on the kidneys (pg.231)
Sjorgen syndrome
Dry eyes, dry mouth via destruction of the lacrimal and salivary glands, can be primary or secondary, commonly with RA--rheumatoid factor and ANA . . . probably viral in activation: can lead to lymphoid cancers and lymphoid tumors
Common inheritance of both SLE and Sjorgen syndrome
Certain Class II molecules that promote autoantibodies
Histology of Sjorgen syndrome
Infiltration of lymphocytes in salivary glands, periductal and perivascular . . . later the characteristic nephritis
Scleroderma
Fibrous accumulation in skin, GI, kidneys, heart, etc. Diffuse is rapid and visceral=fatal; limited is in forearms/fingers/face. Unknown cause. Local growth factors constantly stimulate fibroblasts in the face of autoimmune inflammation
CREST syndrome
Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia
Inflammatory myopathies
Autoimmune response to the skeletal muscles
Mixed Connective Tissue Disease
Looks like other autoimmune diseases, but there is almost NO renal involvement and patients respond to corticosteroids
Polyarteritis Nodosa
Necrotic inflammation of blood vessel walls, noninfectopis
Immunodeficiencies
Primary and secondary, either self-inducing or induced by disease, chemotherapy, etc.
Diseases of T-cell defects
Bacterial sepsis, CMV, EBV, VZV, Candida, Pneumocystis jaroveci, aggressive and constantly infected
Diseases of B cell defects
Strep/Staph/Hemo B, viral encephalitis, severe giardiasis, chronic meningitis and sinopulmonary infections
Diseases of granulocyte defects
Staph, Pseudomonas, Candida, Nocardia, Aspergillus
Complement defect disease
Neisserial infections
Primary immunodeficiencies
Manifest in infancy by recurrent infxns. X-linked agammaglobulinemia (-B cells), common variable:, isolated IgA deficiency, Hyper-IgM, DiGeorge, SCID, Wiskott-Aldrich syndrome
X-Linked Agammaglobulinemia
No B cell precursors because BtK is mutated, no maturation beyond pre-B. Shows at 6 mos, infxn with Hemo, Strep, Staph. No antibody production, live vaccines are deadly,no germinal centers, no plasma cells. Immunoglobulin therapy required.
Common Variable ID
normal B cell numbers, no differentiation. Weirdly related to IgA selective deficiency. T cells cannot signal B cells effectively, because B cells lack receptors? Sinopulmonary pyogenic infxns, herpes, giardia
Isolated IgA deficiency
Familial or acquired with toxo, measles, or other viral. Can have asymptomatic, or sinopulmonary/diarrheal infxns. Unknown defect, but often IgA infusion causes anaphylaxis.
Hyper-IgM
T cell disorder where T cells fail to tell B cells to diff. CD40 or CD40L defect that fails isotype switching. Also present with cell-mediated immunofailure, because CD40 is also used to communicate with macrophages. Pyogenic infxns and PJP.
DiGeorge syndrome
No thymus. No parathyroids either due to failure of 3rd and 4th pharyngeal pouch formation. Tetany. Congenital heart defects. Abnormal facies. Deletion of gene on 22q11, part of a larger syndrome.
SCID
Defects in both humoral and cell-mediated immune responses. Thrush and failure to thrive in infancy. Require a bone marrow transplant to survive. Usually an X-linked defect with any part of T cell process, but mostly in major cytokine receptor subunit. Also autosomal recessive.
Wiskott-Aldrich syndrome
X-linked thrombocytopenia, eczema, recurrent infxns, very fatal. Weird loss of IgM while everything else is normal. Normal thymus, no T cells in periphery. Defect in WASP protein that links cytokine receptors to cytoskeleton.
Complement defects
C3 is deadly, later complement results in Neisseria infxns, C1 causes hereditary angioedema. Can also cause paroxysmal nocturnal hemoglobinuria
Three major routes of HIV transmission
Sexual contact, parenteral inoculation, passage from mom to baby
Three routes of pediatric HIV transmission
1. Transplacentally in utero
2. Delivery via birth canal
3. Ingestion of infected breast milk
Dominant HIV form
HIV-1.
4 major contents of HIV core
Major capsid protein p24, nucleocapsid protein p7/9, two copies of genomic RNA, three viral enzymes (protease, reverse transcriptase, integrase). p24 is used in HIV diagnosis
M-tropic HIV
Infect monocytes/macroophages and freshly isolated peripheral T cells, but not T cells in blood--infects via CCR5. M cells may be more "infectious." M-tropic strains will evolve, in infection, to T-tropic strains
T-tropic HIV
Can only infect T cells, infects via CXCR4. Consider more "progressive" disease-causing than M-tropic.
Major disadvantage (to humans) of M and T tropism of HIV
As our immune systems are activated, obviously, the virus can thrive in the new source of cells (monocytes, T cells) to infect. And the inflammation is caused by HIV itself. Very effective.
Three phases of the natural history of HIV infection
1. Acute retroviral: viremia and lymphoid seeding. Self-limited acute illness that is ultimately controlled
2. Chronic: Continuous HIV production, asymptomatic, minor opportunistic infections
3. AIDS: Total immune breakdown, opportunistic indicator diseases, fever/malaise/weight loss, death
What contains the acute phase HIV infection?
CD 8 cells specific for HIC
Most common pathogens of HIV (complete list on 255)
Candida, CMV, mycobacteria, cryptococcus, toxo, cryptosporidium, herpes, histo. Also tumors such as Kaposi sarcoma, cervical/anal cancer
Kaposi sarcoma
Proliferation of spindle cells from blood vessels from autocrine cytokines and HIV T cells, cause linked to KS herpesvius but genesis unknown
Three kinds of AIDS-related lymphomas
Systemic, CNS, body cavity (location defined)
Amyloid
Proteinaceous pathological substance, deposited between cells all over the body. Not a single definitive protein, but has three major forms. Uniformly organized, though
Physical appearance of amyloid
Nonbranching fibrils made of cross-linked beta-pleated sheets.
Chemistry of amyloid fibrils, 3 most common
1. AL: amyloid light chain made from plasma cells out of immunoglobulin lambda light chain
2. AA: unique liver-synthesized protein: secondary amyloidosis
3. ABeta: Alzheimer's lesion, comes from amyloid precursor protein
What is amyloidosis?
Primary: associated with immunocyte dyscrasia
Secondary: associated with chronic inflammation or tissue destruction
Familial: organ involvement patterns
What causes amyloidosis?
Abnormal protein folding, often as a result of plasma cell tumors, that causes deposition and interruption of normal function. Systemic or Local. Misfolded proteins have a tendency to aggregate. Mechanisms of degradation appear to fail. Very poor prognosis.