Immunology Flashcards
Name the components of innate immunity
- Epithelial barriers
- Phagocytic cells (macrophages, neutrophils)
- Dendritic cells
- Natural Killer cells
- Plasma proteins (complement system, mannose binding lectin, C-reactive protein)
Name 3 HLA alleles and their associated inflammatory diseases
B27 : Ankylosing spondylitis, postgonoccoal arthritis, acute anterior uveitis
DR4: Rheumatoid arthritis
DR3: Chronic active hepatitis, Sjogren syndrome, Type 1 DM
HLA-BW47: 21-hydroxylase deficiency
What are the functions of the components of the innate immune system?
- Skin barriers: mechanical barrier of entry by microbes, anti-microbial molecules (defensins)
- Monocytes/neutrophils: rapidly recruited to site of infection; ingest microbes (recognise molecules released by injured cells, Toll-like receptors, mannose, opsonins) activate NF-kB and increase cytokine production
- Dendritic cells: produce type 1 interferons, antiviral cytokines inhibiting viral replication and infection
- NK cells: mediate antiviral defense by stimulating macrophages
- complement: opsonization, triggers adaptive immune system
Name 3 types of lymphocytes and their function.
B lymphocytes: differentiate into plasma cells, secrete antibodies in response to microbe CD4+ Helper T: recognize phagocytosed antigen, secrete cytokines to activate macrophages, attract leukocytes, stimulate B lymphocytes to produce antibody (MHC class 2) CD8+ cytoxic T: Recognize infected cells and kill them (MHC class 1)
What are the components of adaptive immunity?
Humoral immunity: protects against extracellular microbes, B-cell lymphocytes sand antibodies
Cell-mediated: defense against intracellular microbes, T-cell lymphocyte mediated, effector T and memory cells
What is the makeup of a T-cell receptor complex?
- Disulfide linked heterodimer, made up of alpha and beta polypeptide chain, each with variable region and constant region
- linked non-covalently to 5 polypeptide chains, forming the CD3 complex and the xi chain dimer (invariant)
- other proteins expressed to assist complex include CD4, CD8, CD2, integrins, CD28
What is the role of the T-cell receptor and how does it acquire its function?
- The AB TCR recognizes peptide antigens that are displayed by MHC molecules on the surfaces of APC
- TCR diversity generated by somatic rearrangement of genes coding for TCR A and B genes, during T-cell development in thymus
- Enzyme mediating recombination is RAG-1, RAG-2 (recombination activating genes)
- Individuals able to recognize wide variety of antigens
- T cells recognize both the antigen-MHC complex and signals provided by APCS
What are the components of the B-cell antigen receptor complex?
- Membrane-bound antibodies (IgM, IgD) are present on surface of all mature, naive B cells bind the antigen
- Unique antigen specificity determined by RAG-mediated gene rearrangement
- Two invariant proteins called Igalpha and IGbeta, essential for signal transduction through antigen receptor
- other molecules include complement receptors, FC receptors, CD40
Name 2 types of dendritic cells, location and their functions.
- Interdigitating dendritic cells: antigen presenting cells, express microbe-capturing receptors, recruitment to T-cell zone of lymphoid tissue, activation of CD4+ T cells. Located in skin (Langerhans) and intersitium.
- Follicular dendritic cells: Fc receptors for IgG and C3b and trap antigen bound to antibodies/complement. Present antigen to B cells. Found in germinal centres of lymph nodes/spleen.
Name 3 functions of macrophages.
- function as APCs after phagocytosing microbes
- kill ingested microbes after T cell activation (cell mediated)
- phagocytose and destroy opsonized microbes (IgG/C3b) (humoral)
Outline the function and regulation of NK cells
- Ability to kill infected and tumor cells without prior exposure to these cells AND to lyse IgG coated target cells
- Express CD16 and CD56
- regulated by signals from activating and inhibitory receptors
- Inhibitory: recognizes Self class 1 MHC, not activated
- Activation: NKG2D receptor recognizes cells damaged by infection/DNA damage, reduced self class 1 MHC=killing
- Secrete cytokines (interferon gamma) to activate macrophages
- IL2, IL-15 stimulate proliferation of NK cells
- IL-12 activates killing and production of interferon gamma
Name chemokines involved in migration of T cells
- L-selection, integrin on high endothelial venules to get Naive-T to lymph nodes
- CCL-19, CCL21 bind to CCR7 on T cells, enhacing adhesion and inducing migration through endothelial wall
- E-selection, P-selectin, integrins, CXCL10 to get activated T to site of infection
Describe the 2 classes of MHC molecules and their structure
- Role is to display peptide fragments of proteins for recognition by antigen-specific T-cell
- genes encoding MHC on chromosome 6
- MHC 1, MHC2 and genes encoding complement components, TNF, lymphotoxin
- MHC1: all nucleated cells and platelets, 3 loci: HLA-A, HLA-B, HLA-C
- Heterodimer of polymorphic alpha (hc) and non-polymorphic beta
- Extracellular alpha has 3 domains: A1, A2, A3 (binding in cleft formed by A1/A2
- Display peptides derived from viral antigens found INSIDE cells, and are recognized by CD8+ T lymphocytes. CD8 is a coreceptor.
- MHC 2: 3 loci HLA-DP, HLA-DQ, HLA-DR.
- Heterodimer of Alpha and Beta chains, both polymorphic
- extracellular variable regions have a1, A2, B1, B2 with A1/B1 binding cleft
- Present antigens internalized into vesicles by endoytosis, usually extracellular microbes and soluble proteins
- B2 domain has binding site for CD4, respond to T-cell help
Name 5 cytokines of innate immunity and 5 of adaptive immunity
Innate: TNF, IL-1, IL-12, Type 1 interferons IFN gamma (made by macrophages, dendritic cells, NK)
adaptive: IL-2, IL-4, IL-5, IL-17, IFN-gamma (made by CD4 T cells)
What are the main steps in cell mediated immunity?
- Antigen capture and transport to lymphoid organs by dendritic cells
- Antigen recognition in lymphoid organs (CD4+ helper and CD8+ cells cytotoxic)
- T cell proliferation and differentiation (Naive T cell–>APC–>IL-2–>differentiation in to effector and memory T cells)
- Differentiated effector and memory T cells enter circulation
- Migration of effector T- cells to site of antigen
- CD4+ ( Th1 and TH17 recognize phagocytes with microbes, secrete cytokines leading to recruitment of inflammatory cells, macrophage activation and killing of microbes)
- CD8+ (CTLs recognize MHC2-cells, kill infected cells)
Name 3 types of helper T cells, cytokines produced, reactions triggered, microbes affected, role in disease
TH1: IFN-gamma, activates macrophages, stimulates IgG, good for intracellular microbes, role in autoimmune disease
TH2: IL-4, IL-5, IL-14, stimulates IgE, activates mast cells and eosinophils, good for helminths, role in allergies
TH17: Il-17, IL-22chemokines, recruits neutrophils and monocytes, good for extracellular bacteria and fugi, role in autoimmune disease
Describe the main steps in humoral (B-cell mediated) immunity
- Naive B cell is confronted with microbe, expresses IgM and IgD
- TH express CD40 ligand and cytokines=activate B cells
- B cells proliferate and differentiate into antibody secreting cells, with class switching depending on the type of microbe (IFN-gamma, IL4)
- Affinity maturation=improves quality of humoral response
- Memory cells also generated
- Antibody secreted: neutrolizes microbes/toxins, opsonizes for phagocytosis (recognition of FC portion of IgG by macrophages and NK cells), activates complement, induces inflammation
What are specific roles of isotypes of antibodies?
- IgM: polysaccharides/lipids, neutrolizes microbes/toxins and activates complement
- IgG: activates complement, Fc portion recognized by NK cells and phagocytes, crosses into placenta and protects fetus
- IgA: secreted by mucosal epithelia, neutrolized microbes in lumens of GI/respiratory tract
- IgE: works with eosinophils to kill parasites, by release of eosinophil granule (TH2 cells secret cytokines to stimulate IgE)
Classify hypersensitivity reactions, name a representative disorder, give immune mechanism and pathologic lesions
Type 1: Immediate hypersensitivity, anaphylaxis, production of IgE antibody=release of vasoactive amines and mast cell mediators followed by recruitment of inflammatory cells. Lesions include vascular dilation, edema, smooth muscle contraction, mucous, tissue injury
Type 2: Antibody mediated, Goodpasture syndrome, production of IgG, IgM=biding of antien on target cell, phagocytosis of target cells or bc of complement or FC receptor, recruitment of neutrophils. Lesions include phagocytosis/cell lysis, inflammation
Type 3: Immune-complex mediated, Lupus, serum sickness, Deposition of antigen-antibody complexes=complement activation, recruitment of leukocytes, release of enzymes. Lesions include necrotizing vascuylitis, inflammation
Type 4: Cell mediated (delayed), contact dermatitis, IBD. Activated T lymphocytes=release of cytokines and macrophages activated, T-cell mediated cytotoxicity. Lesions include perivascular infiltrates, edema, granulomas
Describe the sequence of events in type 1 hypersensitivity reactions
- Exposure to allergen
- Activation of TH2 cells and IgE class-switching in B cells
- Production of IgE by B cell
- Binding of IgE to FC portion of E receptor on mast cells
- Repeat exposure to allergen
- Activation of mast cell and release of pre-formed mediators
(mediators include vasoactibev amines, lipid mediators and cytokines) - Immediate hypersensitivity reaction (vasoactive amines) and late-phase reaction (cytokines)
Other than IgE, what are other mast cell secretatogues?
- Complement components C5a and C3a
- Chemokines (IL-8)
- Drugs (codeine, morphine, adenosine)
- Physical stimuli (heat, cold, sunlight)
Name some mediators produced by activated mast cells
A. Granule contents: Histamine, proteases (vasodilation, vascular leakage)
B. Lipid mediators: leukotrienes (*most potent vasoactive, also highly chemotactic), prostaglandin D2 (bronchospasm, mucous) platelet activating factor (platelet activation, bronchospasm)
C. Cytokines (late phase, leukocyte infiltration, epithelial damage, bronchospasm)
Describe 3 mechanisms of antibody-mediated injury
- Opsonization of cells by antibodies and complement components, with ingestion by phagocytes
- Inflammation induced by antibody binding to FC receptors of Ig molecules on leukocytes, and complement breakdown products
- Anti-receptor antibodies disturb normal function of receptors
Name 3 examples of antibody-mediated hypersensitivity (Type 2)
A. Transfusion reaction: cells from incompatible donor react and are opsonized by pre-formed host antibody
B. Hemolytic disease of newborn (erythroblastosis fetalis): antigenic difference between mother and fetus, antibodies from mother cross placenta and cause destruction of fetal RBCs
C. Autoimmune hemolytic anemia/agranulocytosis/thrombocytopenia, where antibodies are created to own blood cells
D. Drug reactions where drug attaches to cell surface and Abs are created to the complex
Gives 6 examples of antibody mediated diseases (Type 2 rxns)
- Autoimmune hemolytic anemia
- Autoimmune thrombocytopenic purpura
- Pemphigus vulgaris
- ANCA vasculitides
- Goodpasture syndrome
- Acute rheumatic feber
- Myasthenia gravis
- Graves’ disease
- IDDM
- Pernicious anemia
Give 5 examples of type 3 (immune complex mediated) hypersensitivity, antigen involved and clinical manifestations
- SLE: nuclear antigens, nephritis, arthritis, skin lesions
- Post-streptococcal glomerulonephritis: Strep cell wall antigens, nephritis
- Polyarteritis nodosa: HBV antigens, systemic vasculitis
- Reactive arthritis: bacterial antigens, acute arthritis
- Serum sickness: various proteins, arthritis, vasculitis, nephritis
- Arthus reaction: various proteins, cutaneous vasculitis
Describe the mechanism of immune complex mediated hypersensitivity
- Antibody-antigen complexes produce tissue damage by eliciting inflammation at the sites of deposition
- reaction initiated when antigen combines with antibody in circulation and is deposited in vessel walls
- antigens can be endogenous or exogenous, and deposition can be systemic or localized (eg. kidney, skin, joints).
What factors are involved in formation and deposition of immune complexes?
Formation: introduction of protein antigen triggers immune response, antibodies are formed ~7d after exposure, secreted into blood and react with antigen
Deposition: local vascular alterations, medium-sized complexes, antigen excess, organs where blood is filtered at high pressure to make another fluid (kidney,synovium)
Describe the components (including cytokines) involved in delayed-type hypersensitivity reactions
APC cell presents to CD4+ T-cell
TH1 subset–> produces cytokines IFN-gamma, TNF–>macrophages activation and inflammation
TH17 subset–> produces cytokines IL-17, IL-222–> activate neutrophils
CD8+ cells: detect antigen within cells, leading to cell killing and tissue injury
Give 5 examples of T-cell mediated (type 4) hypersensitivity rxns, antigen, and clinical features
- Type 1 DM: pancreatic islet B cells–>chronic inflam in islets, B-cell destruction, diabetes
- Multiple sclerosis: protein antigens in CNS myelin (myelin basic protein)–> demyelination in CNS with perivascular inflammation
- Rheumatoid arthritis: antigen in joint synovium ? type 2 collagen–> chronic arthritis with inflammation
- Crohn disease: unknown, ? bacterial–> chronic intestinal inflammation
- Contact dermatitis: various environmental antigens–>skin inflammation with blisters
List immune mediated inflammatory diseases under ab/immune complex and T-cell mediated
AB:hemolytic anemia, thrombocytopenia, myasthenia gravis, Graves’ disease
Immune complex: SLE, polyarteritis nodosa
T cell: DM-1, MS, RA, Sjogren, IBD, inflammatory myopathies
What gene is the most frequently implicated in autoimmunity?
PTPN-22, encodes protein tyrosine phosphatase and is associated with rheumatoid arthritis, DM-1, others
Polymorphisms in gene encode functionally defective, which cannot regulate tyrosine kinases, leading to excessive lymphocyte activation
What is the role of susceptibility genes in autoimmune disorders?
- Multigenetic
- HLA genes are associated
? particular MHC alleles affect negative selection of T ell in thymus OR regulatory T cells (unproven)
