Hypersensitivity. Hypersensitivity reactions An immunological responses not controlled by normal regulatory mechanism. Classification - Gell and Coombs

  • View
    233

  • Download
    0

Embed Size (px)

Text of Hypersensitivity. Hypersensitivity reactions An immunological responses not controlled by normal...

  • Hypersensitivity

  • Hypersensitivity reactionsAn immunological responses not controlled by normal regulatory mechanism.Classification - Gell and Coombs system

  • Gell and Coombs systemType I immediate (Ig E)Type II antibody mediated (ADCC)Type III immune complex mediated Type IV T cell mediated (delay type hypersensitivity)

  • OUTLINEHypersensitivity -mechanism (Sensitization phase/Effect phase) -clinical manifestation -lab testing

  • Type I - immediate hypersensitivity IgE-mediated reactionsMechanism :

    IgESolubleAntigenFcROn mast cells or basophils

  • degranulationCross linking of Fab

  • Type I - immediate hypersensitivity IgE-mediated reactionsclinical manifestationAtopy:Genetically linkage-Allergies-Allergic rhinitis-Asthma-Atopic dermatitis

    -Allergic gastoenteropathy

    Lack genetic linkage and target organ :-Urticaria -Anaphylaxis-Anaphylacic shock

  • Allergic rhinitis

  • Allergic rhinitis

  • Type I - immediate hypersensitivity IgE-mediated reactionsallergenHost dust, arthropod, mold, weeds (ragweed), pollen, tree, animal, food, drug, latex

    Inhalant allergenContact allergenFood allergen

  • Type I - immediate hypersensitivity IgE-mediated reactionsLab test Skin testIn vitro testsLymphocyte stimulationIntranasal provocative tests

  • Skin testCutaneous test (prick test) pucture small amount to dermis and read after 20 minIntradermal test semiquantitative

  • In vitro testsTotal IgE : IMMULITE Total IgE (serum IgE only)Allergen specific IgE RAST : radioallergosorbent test MAST : multiple antigen simultaneous test CAP Immunoblot (AlaBLOT test) --allergen: Ep stripEosinophilia : 114-142 300-500/mm3ECP (eosinophil cationic protein)

  • MAST(Multiple Antigen Simultaneous Test)36Chemical Luminescent ImmunoAssay

    Allergen + tested IgE Allergen-IgE-(Anti-IgE) CLA-1

    : 4 : >2423 : 143~2422 : 66~142 1 : 27~65: 12~26- : 0~11

    Anti-IgE*Enzyme( : LUs)Total IgE>500 IU/mL MASTnon-specific binding

  • Principle Chemiluminescence Analysis ()

  • MAST allergy testIntroduction 36IgE (LUs)

    Result 0, 0/1, 1, 2, 3, 4 2

    Clinical significance Atopic allergy IgE

  • MAST 36

  • CAPcellulose carriers-GalactosidaseIgE,,CAP

    -Galactosidase

  • CAP(23)(6)

  • CAP(23)(6)

  • UniCAP

  • UniCAP : FEIAFluorescence Enzyme Immunoassay (FEIA)

    Enzyme : -galactocidaseSubstrate : 4-MUG 4-MUStop Solution : 4% Sodium Carbonate

  • UniCAPFEIAAutoantibody(Specific IgG)(Total IgE, Specific IgE)Total IgEIgE : 2~5000 kU/LSpecific IgEIgE (23)(6)

    Cyclic cirtullinared peptide(CCP) AbExtractable Nuclear Antigen Ab(ENA)

  • Eosinophil cationic protein(ECP)Anti-ECPcellulose carriers(), ,, -GalactosidaseECP, ,CAP

    eosinophilECP,(ex.),,ECP

    Anti-ECP

  • Type I - immediate hypersensitivity IgE-mediated reactionsTherapyEnvironmental measures : avoid allergenpharmacological therapies -antihistamine -corticosteroids -cromolyn sodiumDesensitization treatment -Allergen shots (blocking antibody, IgG) Antibody against free and membrane IgE Antibody to CD23 (low affinity IgE receptor)Cytokine intervention

  • Type II antibody mediatedMechanism :1.Cell surface antigen Transplanted cell Host cell (autoimmune) Foreign antigen bind to host cells

    2.IgM IgG production (dep. on cytokine)

    Sensitization phase 1.Complement activation chemoattractant C5a C3a Anaphylatoxin C5a Opsonin MAC 2.ADCC by NK3.Opsonin mediated phagocytosis

    Effect phaseAg dose not clear from systemDestory cellsIgGIgM

  • IgG IgM

  • Type II antibody mediatedclinical manifestation (dep. on cell type)-Hemolytic disease of newborn-Transfusion reactions-Autoimmune disorders-Drug induced reactions-Transplantation

  • Hemolytic disease of newbornRBC-Rh antigen

  • Autoimmune disorderGoodpastures syndrome Ab against kidney and lung basement membranes Antiglomerular basement membrane antibody (Anti-GBM) renal biopsy even layer on the glomerular basement membrane

  • Myasthenia gravis Ab against acetylcholine receptor in neuromuscular junctions down regulation of receptors by endocytosis muscle weakness

  • Drug induced reactionsex : penicillin

    Drug (hapten) Bind to cell surface Type II hypersensitivity Cell destruction

  • Type III-immune complex mediatedSensitization phase 1.Chronic Ag (soluble) exposure autoimmue disorders or persistent infection 2.IgM IgG production (dep. on cytokine)

    Too many immune complexesfor phagocytesto removeImmune complex formationand deposition in the capillary wallsIgGIgMMechanism :

  • 1.Complement Anaphylatoxin C5a Opsonin C3b CR1 chemoattractant C5a C3a2.Neutrophil phagocytosis damage capillary walls (proteolytic enzyme)3.Coagulation Vascular permeability PLA aggregation blood clot formation *4.Immune complexes penetrate and lodged in capillary walls 5.Vascular occlusionEffect phaseType III-immune complex mediatedIgGIgM

  • Type III-immune complex mediatedclinical manifestation -SLE autoantibody, immune complexes deposit in various tissues -Post streptococccal glomerulonephritis S. pyogenes, kidney, captured antigen -Serum sickness passive immunization of non human IgG human antibody non human IgG (ex:horse serum:anti-diphtheria antibodies, antiserum administered following a snakebite ) -Farmers lung Ag = spore of Thermophilic actnomycetes -Arthus Reaction Non human IgG

  • Serum sickness

  • Arthus ReactionAg inject into immunized bodyLocal inflammatory response due to deposition of immune complexes in tissues. vaccine boosting(2)

  • Detection of Immune ComplexC1q binding assayRaji cell assayDetection of Cryoglobulins

  • C1q binding assay

  • C1q binding assay

    False (-)Small immune complex IgE, IgA, IgG4 immune complexFalse (+)FibrinogenfibronectinDNAendotoxinheparin

  • Raji cell assayLymphoblastoid cell line from Burkitts lymphomaC1q C3b C3d and Fcg receptor

    Normal:

  • Raji cell assayFalse-positives occur when antilymphocyte antibodies are present. Especially in SLE, positive results often reflect the presence of lymphocyte antibodies. Raji assay are commonly found in systemic necrotizing vasculitis and might be useful for monitoring sarcoidosis().

  • Detection of CryoglobulinsCryoglobulins are abnormal immunoglobulins which form complexes and precipitate out of serum at low temperatures and resolubilise on warming.4oCresponsible for specific symptoms,such as Raynauds phenomenon, vascular purpura, bleeding tendencies, cold-induced urticaria

    http://www.labcorp.com/datasets/labcorp/html/chapter/mono/sc029100.htm

  • Detection of Cryoglobulins

    Type of Cryoglobulin Immunochemical Composition Type 1 : Single monoclonal immunoglobulins IgM IgG IgA Monoclonal light-chains Type II : Mixed monoclonal immunoglobulins IgM-IgG IgG-IgG IgA-IgG Type III : Mixed polyclonal immunoglobulins IgM-IgG IgM-IgG-IgA

  • Detection of Cryoglobulins

    Type 1 : Single monoclonal immunoglobulins Myeloma Waldenstroms Chronic Lymphocytic Type II : Mixed monoclonal immunoglobulins Myeloma Waldenstroms Macroglobulinaemia Chronic Lymphatic Leukaemia Type III : Mixed polyclonal immunoglobulins Autoimmune Disease: Lupus (SLE) Rheumatoid arthritis Scleroderma Sjogrens Syndrome Chronic active hepatitis Active Hepatitis. Post streptococcal nephritis. Vasculitis Infections:

  • Type IV T cell mediated delayed-type hypersensitivity, DTH Sensitization phase Effect phase

  • Type IV T cell mediated macrophage activation clinical manifestation chronic DTH -Mycobacterium tuberculosis acute DTH (24-48 hr.) -Mantoux skin test (PPD= purified protein derivative)

  • Contact dermatitis

  • Mycobacterium tuberculosis TB prevent fusion of lysosomes and phagosomes TB live in macrophage macrophage destruction chemotatic factors release chemotasis Tubercle

  • Type IV T cell mediatedLabpatch test (read after 48 hr.): PPD or tuberculin skin test (Koch phenomena) Candida albicans Streptokinase Mumps Trichophyton

  • The DTH skin test: Mantoux testDetermine the infection of Mycobacterium tuberculosis

    PPD24-48 hr.(PPD= purified protein derivative)

  • summary

    Sensitization phaseEffectphaseClinical Type I ImmediateSolubleAntigenIgEIgE cross-linked with AgMast cells and basophils degranulationAllergies Rhinitis AsthmaAnaphylaxis Anaphylacic shock UrticariaType IIAb mediatedCell surfaceAntigenIgM IgGAb bind to surface Ag*Complement*ADCC by NK*phagocytosis(Opsonin) cell destructionHemolytic disease of newbornGoodpastures syndrome Myasthenia gravis Drug induced reactionTransfusion reactionTransplantation Type IIIImmune complex mediatedSolubleAntigen(many)IgM IgGAb bind to free Ag immune complexImmune complex deposited in capillary wall localized destructionSLE Post streptococccal glomerulonephritis Serum sicknessPersistent infection Farmers lungType IVCellmediatedNave CD4 T cell activationMacrophageDTHContact sensitivityDelay hypersensitivityImmunity to viral and fungal antigens and intracellular organismsRejection of foreign tissue graftsElimination of tumor cells bearing neoantigen