HYPERSENSITIVITY REACTIONS D R S H O AI B R AZ A

HYPERSENSITIVITY REACTIONS D R S H O AI B R AZ A

HYPERSENSITIVITY REACTIONS Are exaggerated immune response upon antigenic stimulation Individuals who have been previously exposed to an antigen are said to be Sensitized Repeat exposure to same antigen may trigger a pathologic reaction Implying an excessive response to an antigen

GENERAL CONSIDERATION Both exogenous and endogenous antigens may elicit reaction Dust, pollen, foods, drugs, microbes, chemicals Autoimmune disorders against self antigens Reactions are often associated with inheritance of particular susceptible gene(hla-gene) Reflects an imbalance between the effector mechanism and control mechanisms of immune responses.

CLASSIFICATION Classification is based on Immunologic mechanism that mediate the disease Multiple mechanisms may be involved Classified into Type I (Immediate type) Type II (antibody mediated) Type III (Immune complex mediated) Type IV (cell mediated )

TYPE I HYPERSENSITIVITY REACTION Immediate type HR Rapid immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen Often called as ALLERGY Systemic disorder: Local reactions: Immediate or initial reaction Late phase reaction

Most Type I HR are mediated by IgE dependent activation of the mast cells, and other leukocytes Mast cells: Bone marrow derived Abundant near vessels, nerves Cytoplasm has membrane bound granules Acid proteoglycans Histamine Have high affinity for FcIgE Activation may be through C5a and C3a

Mast cell activation occur through FcIgE C5a, C3a (anaphylatoxin) Chemokines e.g. IL-8 Drugs (e.g. codeine, morphine adenosine etc) Mellitin (present in venom) Physical stimuli heat, cold, sunlight

MECHANISM Immediate type hypersensitivity reaction Primary exposure: Exposure to antigen (allergen e.g. pollen) Activation of TH2 cells and IgE production by B-Cells Production of IgE IgE binds to allergen Immune complex binds through Fc to mast cells Mast cells become sensitized Secondary exposure: Allergen binds to IgE present on sensitized mast cells Activation of mast cells Release of mediators

MEDIATORS OF MAST CELLS Preformed Mediators: Vasoactive amines Histamine Enzymes (chymase, tryptase, acid hydrolase) Proteoglycan Lipid Mediators: Synthesized in mast cell membranes LT C4, D4 LT B4 PGD2 PAF Cytokines: TNF, IL-1

ACTIONS OF MAST CELL MEDIATORS Vasodilation, increased vascular permeability Histamine, PAF, Lt C4, D4, E4, Neutral proteases, PGD2 Smooth muscle spasm LT C4, D4, E4, Histamine, Prostaglandins, PAF Cellular infiltration Cytokines (TNF, etc), LTB4, Eosinophil and neutrophil chemotactic factors,

It is a complex disorder resulting from an IgEmediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition. These events are regulated mainly by the induction of TH2 helper T-Cells that stimulate production of IgE, cause accumulation of inflammatory cells, and trigger secretion of mucus. The clinical features result from release of mast cell mediators as well as the eosinophil rich inflammation.

CLINICAL EXAMPLES Systemic anaphylaxis: Vascular shock, generalized edema, dyspnea Antisera, hormone, enzyme administration Food allergens Skin erythema, itching, followed by bronchospasm occur within minutes after exposure Laryngeal edema may lead to death Local immediate Hypersensitivity Reaction: Pollen, animal dander, house dust, foods, etc Specific disease include urticaria, angioedema, allergic rhinitis, bronchial asthma

TYPE II HYPERSENSITIVITY REACTION Antibody mediated hypersensitivity reaction Antibody react with antigens Present on the cell surface In the extracellular matrix The antigenic determinants may be Intrinsic Extrinsic or exogenous (drug metabolites) Either of three mechanisms: Opsonization and phagocytosis (ADCC) Complement and Fc receptor mediated inflammation Cellular dysfunction

OPSONIZATION & PHAGOCYTOSIS Responsible for depletion of cells coated with antibodies Cells opsonized by IgG are recognized by phagocyte Fc receptor When IgG or IgM deposited on cell surface, complement may be activated forming C3b Phagocytosis of the opsonized cell and their destruction Complement activation may lead to formation of membrane attack complex Antibody dependent cellular toxicity Clinically characterized by Transfusion reaction HDN (erythroblastosis fetalis) Autoimmune hemolytic anemia

INFLAMMATION Antibodies deposit in fixed tissues (BM, ECM) Deposited antibodies activate complement C5a Chemotaxis of neutrophil C3a & C5a Increase vascular permeability Leukocyte activation results in protease release Clinically characterized by Glomerulonephritis Graft Rejection

CELLULAR DYSFUNCTION Antibodies directed against cell surface receptor (anti-receptor antibody) Impair or dysregulate functions Clinically characterized by Myasthenia gravis Anti-acetylcholine receptor antibody blocks neuromuscular transmission and causes muscle weakness Grave s Disease Anti TSH receptor antibody stimulate the cell, resulting in hyperthyroidism

TYPE III HYPERSENSITIVITY REACTIONS Immune-complex mediated hypersensitivity reaction Antigen antibody complexes produce tissue damage mainly by eliciting inflammation Circulating immune complex In-situ immune complexes (planted antigen) Antigen may be Endogenous Exogenous Disease can be Systemic (SLE) Localized (RA, GN)

SYSTEMIC IMMUNE COMPLEX DISEASES Acute serum sickness is the prototype Disease develops in three phases Immune complex formation Circulating immune complexes are formed Deposition of immune complexes Tissue injury by immune complexes Initiation of acute inflammatory reaction Characterized by: Vasculitis Glomerulonephritis Arthritis

LOCAL IMMUNE COMPLEX DISEASE Prototype is Arthus Reaction Localized area of tissue necrosis resulting from Acute immune complex vasculitis

TYPE IV HYPERSENSITIVITY REACTION Delayed type or T-cell mediated type hypersensitivity reaction Initiated by antigen activated (sensitized) T-Cells CD4+ or CD8+ T-Cells CD4+ T-Cells mediated hypersensitivity can be a cause of chronic inflammatory diseases CD8+ T-Cells may also be involved In certain viral infections CD8+ T Cells may be the predominant cells

EXAMPLES Disease Specificity of pathogenic T- Cells Type I diabetes Antigens of pancreatic β cells Clinicopathologic manifestations Insulinitis; diabetes Multiple sclerosis Protein in CNS myelin Demyelination in CNS; paralysis, ocular lesions Rheumatoid arthritis Unknown antigen in joint synovium Chronic arthritis Crohn disease Unknown antigen Chronic intestinal inflammation (granuloma) Contact dermatitis Environmental antigens Skin inflammation with blisters Tuberculin test PPD of M. tuberculosis Indurated swelling

REACTION OF CD4+ T-CELLS Delayed type hypersensitivity and immune inflammation Chronic inflammatory reactions against self antigens Proliferation & differentiation of CD4+ T Cells IL-2, TH1 or TH17, IFN-γ, TGF-β Response of differentiated effector T-Cells IFN-γ secreted by TH1 responsible for Activated macrophages are altered Increased expression of class II MHC Morphologically characterized by Accumulation of mononuclear cells (Granuloma formation)

REACTION OF CD8+ T-CELLS CD8+ T-Cells (CTL)kill antigen bearing target cells CTL directed against cell surface histocompatibility antigens important in graft rejection Killing of virally infected cells presenting MHC I Perforins facilitates release of granzyme Granzyme activate caspases Produce IFN-γ, and involve in inflammatory reactions

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