Lec 57: Introduction to Hypersensitivity Flashcards
Type I (immediate) hypersensitivity
IgE antibody-mediated activation of mast cells (effector cells) produces an inflammatory reaction. IgE antibody production (sensitization), mast cell activation (re-exposure).
Sensitization
allergens are first processed by APCs. APCs interact with CD4 Th2 cells, causing interleukins to stimulate B-cell maturation. IL-4 causes plasma cells to switch from IgM to IgE synthesis. IL-5 stimulates the production and activation of eosinophils.
Re-exposure
allergen-specific IgE antibodies are bound to mast cells. allergens cross-link IgE antibodies specific for the allergen on mast cell membranes. IgE triggering causes mast cell release of preformed mediators (1. early phase reaction with release of histamine, chemotactic factors for eosinophils, proteases. 2. produces tissue swelling and bronchoconstriction). late phase reaction (1. mast cells synthesize and relase prostaglandins and leukotrienes. 2. enhances and prolongs acute inflammatory reaction).
Type II hypersensitivity
antibody-dependent reactions
Complement-dependent reactions
lysis (IgM-mediated), lysis (IgG-mediated), phagocytosis
Lysis (IgM-mediated)
antibody (IgM) directed against antigen on the cell membrane activates the complement stem, leading to the lysis of yhe cell by the membrane attack complex (MAC). ex: IgM types of cold immune hemolytic anemias, transfusion of group A blood (contains anti-B-IgM antibodies) into a group B individual
Lysis (IgG-mediated)
IgG attaches to basement membrane/matrix–>activates complement system–>C5a is produced (chemotactic factor)–>recruitment of neutrophils/monocytes to the activation site–>release of enzymes, reactive oxygen species–>damage to tissue. ex: goodpasture’s syndrome with IgG antibodies directed against pulmonary and glomerular capillary basement membranes, acute rheumatic fever with IgG antibodies directed against antigens in hear, skin, brain, subcutaneous tissue, joints.
Phagocytosis
fixed macrophages (eg. in spleen) phagocytose hematopoietic cells (eg. RBCs) coated by IgG antibodies or complement (C3b). ex: warm (IgG) immune hemolytic anemia, ABO hemolytic disease of the newborn (group O mother jas anti-A, B-IgG antibodies that cross the placenta and attach to getal blood group A or B RBCs)
Complement-independent reactions
antibody (IgG)-dependent cell mediated cytotoxicity, antibody (IgE)-dependent cell-mediated cytotoxicity, IgG autoantibodies directed against cell surface receptors–>impair function of the receptor (eg. anti-Ach receptor antibodies in myasthenia gravis) or stimulate function (eg. anti-TSH receptor antibodies in Graves’ disease).
Antibody (IgG)-dependent cell-mediated cytotoxicity
cells are coated by IgG–>leukocytes (neutrophils, monocyte, NK cells) bind to igG–>activated cells release inflammatory mediators causing lysis of teh cells. ex: killing virus-infected cells or tumor cells
Antibody (IgE)-dependent cell-mediated cytotoxicity
helminth in tissue is coated by IgE antibodies–>eosinophil IgE receptors attach to IgE–>eosinophils release major basic protein, which kills the helminth
Tests used to evaluated type II hypersensitivity
direct Coombs’ test detects IgG and C3b attached to RBCs. Indirect Coombs’ test detects antibodies (eg. anti-D) in serum
Type III hypersensitivity
activation of teh complement system by circulating antigen-antibody complexes (eg. DNA-anti-DNA complexes). first exposure to antigen–>synthesis of antibodies. second exposure to antigen–>deposition of antigen-antibody complexes, complement activation, producing C5a, which attracts neutrophils that damage tissue. Arthus reaction
Arthus reaction
localized immunocomplex reaction. ex: farmer’s lung from exposure to thermophilic actinomycetes, or antigens, in air.
Type IV hypersensitivity
antibody-independent T cell-mediated reactions (cellular-mediated immunity, CMI)
Functions of CMI
control of infections caused by viruses, fungi, helminths, mycobacteria, intracellular bacterial pathogens. graft rejection. tumor surveillance
types of reactions
delayed reaction hypersensitivity (DRH), cell-mediated cytotoxicity
Delayed reaction hypersensitivity (DRH)
CD4 cells interact with macrophages (APCs with MHC class II antigens), resulting in cytokine injury to tissue
Cell-mediated cytotoxicity
CD8 T cells interact with altered MHC class I antigens on neoplastic, virus-infected or donor graft cells, causing cell lysis. contact dermatitis–activated CD4 and CD8 T cells damage antigens in skin (eg. poison ivy, nickel)
Type I Hypersensitivity
IgE-dependent activation of mast cells.
Atopic disorders: hay fever, eczema, hives, asthma, reaction to bee sting.
Drug hypersensitivity: penicillin rash or anaphylaxis
Type II Hypersensitivity
Antibody-dependent reaction.
Complement-dependent reactions
Lysis (IgM mediated): ABO mismatch, cold immune hemolytic anemia;
Lysis (IgG mediated): Goodpasture’s syndrome, Pernicious anemia;
Phagocytosis: warm (IgG) autoimmune hemolytic anemia, ABO and Rh hemolytic disease of newborn, idiopathic thrombocytopenic purpura.
Complement-independent reactions
Antibody (IgG)-dependent cell-mediated cytotoxicity: natural killer cell destruction of neoplastic and virus-infected cells; Antibody (IgE)-dependent cell-mediated cytotoxicity: eosinophil destruction of helminths; Antibodies directed against cell surface receptors: myasthenia gravis, Graves’ disease
Type III
Deposition of antigen-antibody complexes. Systemic lupus erythematosus (DNA-anti-DNA), Serum sickness (horse antithymocyte globulin-antibody), Poststreptococcal glomerulonephritis
Type IV
Antibody-independent T cell-mediated reactions. Delayed type–tuberculous granuloma; PPD reaction, Multiple sclerosis. Cell-mediated cytotoxicity–killing of tumor cells and virus-infected cells; contact dermatitis (e.g., poison ivy, nickel)
Innate (natural, nonspecific) immunity
nonspecific defense system against microbial pathogens. does NOT confer long-lasting immunity against pathogens
Innate immunity effector cells
phagocytic cells, natural killer (NK) cells, dendritic cells, microglial cells, eosinophils, mast cells, mucosal epithelial cells, endothelial cells
Toll-like receptors (TLRs) in innate immunity
membrane proteins located on the effector cells. recognize non-self antigens commonly shared by pathogens. called pathogen-associated molecular patterns (PAMPs) (ex: endotoxin in gram-neg bacteria, peptidoglycan in gram-pos bacteria). PAMPs are not present on normal host effector cells.
Interaction of TLRs on effector cells with PAMPs
initiates intracellular transmission of activating signals to nuclear factor (NF)kb (NFkb is the “master switch” to the nucleus). genes are encoded for mediator production. mediators are released into the serum or spinal fluid.
innate immunity mediators
nitric oxide, cytokines (TNF, IL-1), adhesion molecules for neutrophils (eg. selectins), reactive oxygen species (eg. peroxide), antimicrobial peptides, chemokines
acquired (specific) immunity
antigen-dependent activation and expansion of lymphocytes. B lymphocytes produce antibodies (ie. humoral immune response). IgM synthesis begins at birth (presence of IgM at birth may indicate congenital infection–eg. CMV). IgG synthesis begins at ~2 months (presence of IgG at birth is maternally derived IgG). T cells are involved in cell-mediated immune responses.
MHC
known collectively as human leukocyte antigen (HLA) system. located on short arm of chromosome 6. gene products are coded for on different loci. gene products are membrane-associated glycoproteins (located on all nucleated cells with exception of mature RBCs). HLA genes and their subtypes are transmitted to children from their parents.
Class I antigens
coded by HLA-A, -B, and -C genes. recognized by CD8 T cells and natural killer cells. altered class I antigens (eg. virus-infected cell) lead to destruction of the cell.
Class II antigens
coded by HLA-DP, -DQ, and -DR genes. present on antigen-presenting cells (APCs–B cells, macrophages, dendritic cells). recognized by CD4 T cells
HLA association with disease
HLA-B27-ankylosing spondylitis, HLA-DR2-multiple sclerosis, HLA-DR3 & -DR4-type I diabetes mellitus
Applications of HLA testing
transplantation workup, determining disease risk (ex: HLA-B27 postive individuals have an increased risk of ankylosing spondylitis).
T cells
CD4 (helper), CD8 (cytotoxic/suppressor). Bone marrow lymphocyte stem cells mature in thymus. located in Peripheral blood and bone marrow, thymus, paracortex of lymph nodes, Peyer’s patches. CD4 cells–secrete cytokines (IL-2 _ proliferation of CD4/CD8 T cells; IFN-_ _ activation of macrophages); help B cells become antibody-producing plasma cells. CD8 cells–kill virus-infected, neoplastic, and donor graft cells
B cells
Bone marrow stem cells. located in Peripheral blood and bone marrow, germinal follicles in lymph nodes, Peyer’s patches. Differentiate into plasma cells that produce immunoglobulins to kill encapsulated bacteria (e.g., Streptococcus pneumoniae). Act as APCs that interact with CD4 cells
Natural killer cells
Bone marrow stem cells. located in Peripheral blood (large granular lymphocytes). Kill virus-infected and neoplastic cells. Release IFN-_
Macrophages
Conversion of monocytes into macrophages in connective tissue. located in Connective tissue; organs (e.g., alveolar macrophages, lymph node sinuses). Involved in phagocytosis and cytokine production. Act as APCs to T cells
Dendritic cells
Bone marrow stem cells. located in Skin (Langerhans’ cells), germinal follicles. Act as APCs to T cells
Autoimmune dysfunction
associated with a loss of self-tolerance, resulting in immune reactions directed against host tissue
Factors that tigger autoimmune disese
Genetic factors:
- autoimmune diseases tend to run in families
- greater incidence of disease in monozygotic (versus dizygotic) twins
- Several diseases are linked with the HLA locus, especially class II alleles
- many genetic polymorphisms are associated with different autoimmune diseases as indicated by genome-wide association studies and family linkage studies
Environmental factors:
- Viruses and other microbes may share cross-reacting epitopes with self antigens so that the responses may be induced by the microbe but it attacks self tissues (molecular mimicry)
- Microbial infections with resultant tissue necrosis and inflammation can cause upregulation of costimulatory molecules on APCs in the tissue
- this favors a breakdown in T cell anergy and leads to T cell activation
Mechanisms of Self Tolerance
Central Tolerance: Immature lymphocytes that recognize self antigens in the central lymphoid organs are killed by apoptosis
Peripheral Toleralance: immunological tolerance developed after T and B cells mature and enter the periphery
Central Tolerance
- B cell lineage: some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive
- Autoimmune regulator (AIRE): putative transcription factor that induce the expression of peripheral tissue antigens in the thymus, thus making the thymus an immunologic mirror of self.
- Mutations in the AIRE gene are responsible for an autoimmune polyendocrine syndrome in which T cells specific for multiple self antigens escape deletion (presumably because these self antigens are not expressed in the thymus), and attack tissues expressing the self antigens
Peripheral Tolerance
Anergy: Mature lymphocytes that recognize self antigens in peripheral tissues become functionally inactive
- Activation of T cells requires two signals: recognition of peptide antigen in association with self MHC molecules on APCs, and a set of second costimulatory signals (e.g., through B7 molecules)
- Costimulatory molecules are not strongly expressed on most normal tissues, so the encounter between autoreactive T cells and self antigens in tissues may result in anergy
Suppression by regulatory T cells: T lymphocytes that recognize self antigens in peripheral tissues are suppressed by regulatory T lymphocytes
- Regulatory T cells express CD25, one of the chains of the receptor for IL-2, and require IL-2 for their generation and survival
- Express transcription factor FoxP3; necessary for the development of regulatory cells, and mutations in the FOXP3 gene are responsible for a systemic autoimmune disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), which is associated with deficiency of regulatory T cells.
- Secretion of immunosuppressive cytokines (e.g., IL-10,TGF-β) can dampenT cell responses, and competitive blocking of B7 molecules on APCs allows Treg to control immune responses
Activation-induced cell death: Mature lymphocytes that recognize self antigens die by apoptosis
- Death receptor Fas (a member of the TNF receptor family) which can be engaged by its ligand coexpressed on the same or neighboring cells causes apoptosis
- Mutations in the FAS gene are responsible for autoimmune lymphoproliferative syndrome (ALPS), characterized by lymphadenopathy and multiple autoantibodies including anti-DNA
IL - 4
Switch B cell from IgM to IgE and stimulate TH2
IL - 5
Induces expansion and activation of Eosinophils
IL - 13
Like IL - 4, promotes class switching from IgM to IgE in B cells, but also stimulates mucus secretions by epithelial cells
Vasodilators
Histamine
PAF
Leukotriene C4 D4 E4
Neutral proteases (activate kinins and complement)
Prostaglandin D2
Smooth Muscle Spasm
Leukotriene C4 D4 E4
Histamine
Prostaglandins
PAF
Cellular Infiltration
Cytokines (chemokines, TNF)
Leukotriene B4
Eosinophil and neutrophil chemotactic factors
Opsonization/Phagocytosis
Complement Bound to Target
IgG/gM Fc Receptor
Complement Activation (C3B)
Type II reactions do what, generally?
Disease tends to be specific to tissue or site where antigen is found
Type III reactions are what, generally?
Can be associated with vasculitis (necrosis usually) and systemic manifestations
What sensitivity reactions do we see necrosis in?
Type 2 and 3
What reactions do we see “Wheal and flare” in?
Type I
What reactions do we first see cell lysis?
Type II
What reaction type do we see induration in?
Type IV
When do we see granuloma formation?
Type IV hypersensitivity
What type of hypersensitivity reaction do we see with Diabetes Type 2?
Type IV Hypersensitivity
