Hypersensitivity MedChula

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Principle of Immunology 3 2554

Hypersensitivity

..

Gell and Coombs Classification

4 , effector molecules

1. Type I hypersensitivity Immediate type (IgE-mediated) hypersensitivity2. Type II hypersensitivity Antibody-mediated cytotoxic hypersensitivity3. Type III hypersensitivity Immune complex-mediated hypersensitivity4. Type IV hypersensitivity Delayed-type hypersensitivity

Type I (Immediate type (IgE-mediated)) hypersensitivity

1

humoral immune response T helper 2 (Th2)

IgE IgE highaffinity Fc receptor mast cell basophil IgE mast cell basophil cross-links IgE sensitized mast cell basophil (Degranulation) (Mediators) 1


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(allergen)(inhalants)

(ingestants) injectants

IgE(cytophilic antibody) FC recetor(FcRI, FcRII) mast cell basophil species homocytotropic antibody

FcRI IgE mast cell basophil

(mediators) processing antigen presenting cell T cell MHC class II Th2 cell B cell plasmacell IgE IgE Fc receptor IgE mast cell basophil sensitization specific IgE cross-linkage (bridging) IgE 2

GTP-dependent stimulatory G-protein (Gs)

adenylate cyclase adenosine triphosphate (ATP) cyclicadenosine monophosphate (cAMP) inactivate protein kinase A activate protein kinase A cAMP protein tyrosine kinase(PTK) phospholipase C phosphatidyl inositol 4,5-bisphosphate(PIP2) inositoltriphosphate(IP3) diacylglycerol(DAG) activate protein kinase A, inositoltriphosphate(IP3) diacylglycerol(DAG) calcium ion( Ca2+) sarcoplasmic reticulum (SER) cytosol DAG activated cytosol protein P DAG DAG-lipase monoacylglycerol(MAG) free fatty acid(FFA) activated cytosol protein P, MAG, FFA cAMP


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methylation phospholipid calcium channel calcium (calcium influx)

Degranulation cAMP MAG, FFA cytosolprotein P (fusogens) (mediators) degranulation mast cell basophil IgE cross-bridging anaphylactoid reaction

o Anaphylatoxin C3a, C4a,C5a

o radio contrast media, morphine, aspirin,chymopapain

o Anti-idiotype antibody anti-isotype antibody intravenousimmunoglobulin

o Anti-Fc receptor antibodyo Ca2+ influx Ca2+ ionophore


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mast cell degranulation

degranulation (mediators) 2

I. (primary or preformed mediators) mast cell basophil degranulation

1. Histamine

decarboxylation histidine histamine receptor 4 H1, H2,H3 H4 receptor 1 histamineH

1receptor,

[vascular permeability] mucous secretion globletcell histamine 1-2 10 histaminase histamine

H1 receptor antihistamine hydroxyzine,chlorpheniramine, diphenhydramine

histamineH2receptor, gastricparietal cell histamine H2 receptor mast cell basophil mast cell basophil negative feedback degranulation mast cell

basophilhistamineH2receptor H2-receptor antagonist ranitidine femotidine

H3 receptor H

1 H

2receptor H

4receptor

neutrophil, eosinophil, basophil, mast cell T helper cell histamine H3 H4 receptorcAMP

2. Eosinophilic chemotactic factor of anaphylaxis [ECF-A]


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LTD4 LTE4 vascular permeability histamine 100

leukotriene prostaglandin

30-60 degranulation mast cell basophil neutrophil,macrophage, eosinophil leukotriene prostaglandin early late phase 1

leukotriene slow-reacting substance of anaphylaxis [SRS-A] histamine

2.2 Prostaglandins [PG] Thromboxanes metabolism arachidonic acid

leukotriene cyclo-oxygenase pathwayprostaglandin permeability prostaglandin prostaglandin D

2[PGD

2]

vasodilatation [wheal and flare]

thromboxane thromboxane A2 [TXA2] thromboxane B2[TXB2] leukotrienes, prostaglandins thromboxanes arachidonic acid pathway pathway pathway non-steroidal anti-inflammatory drugs [NSAIDs] aspirin, diclofenac ibuprofen

cyclo-oxygenase pathway leukotrieneslipooxygenasepathway bronchoconstriction

2.3 Platelets activating factor [PAF]

acetyl glyceryl ether phosphoryl choline [AGEPC] mast cell, basophil, neutrophil, monocyte macrophage vasoactiveamine platelet factor-4 [PL4], histamine, serotonin, thromboxane A2 [TXA2]


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thromboxane B2 [TXB2] PAF histamine 100-1,000 eosinophil

PAF ketotifen

2.4 Kinins

decapeptide protease enzyme kininogens kallikreins kininsbradykinin , vascular permeability mucous gland

2.5 Cytokines

mastcell,basophileosinophil 1 IL-3,IL-4, IL-5, IL-6, IL-10, IL-13 TNF- neutrophil, eosinophil late phase response IL-4 IL-13 Th2 response IgE IL-

5 eosinophil TNF- shock systemic anaphylaxis

4-8 late phase reaction PAF, LTC, IL-4, IL-5, TNF-, ECF-A, NCF-A

anaphylactic shock allergic asthma anaphylactic shock2 anaphylactic shock allergic asthma


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1

Primary mediators Actions

Histamine, heparin ,

Serotonin () ,

Eosinophil chemotactic factor (ECF-A) eosinophil

Neutrophil chemotactic factor (NCF-A) neutrophil

Proteases (tryptase, chymase) vascular basementmembrane ,

Secondary mediators Actions

Leukotrienes (slow reacting substance of

anaphylaxis, SRS-A),

Prostaglandins, Thromboxanes , ,

Platelet- activating factor ,

Kinin ,

Cytokines , adhesion molecule, IgE , systemicanaphylaxis


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1 mediator

1. [bronchospasm]

2. vascular permeability shock intravascular fluid interstitial space

3. mucous secretion 4. late phase reaction5. histamine

1 [systemic anaphylaxis]

1. Anaphylaxis 1 15-30

, , anaphylactic shock epinephrine anaphylaxis , antiserum,

2. Allergic asthma mucus secretion [wheeze] inhalants , , ,


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3. Allergic rhinitis 20%

anaphylaxis typeI hypersensitivity mediators 40-50% (aeroallergen)

4. Allergic conjunctivitisAllergic rhinitis 2

5. Urticaria AngioedemaUrticaria (wheal),

(flare) 1,3 ingestants ,, ,

Angioedema urticaria [dermis] [subcutis], [genitalia] [laryngeal edema]

angioedema bradykinins C1inhibitor deficiency, angiotensin-converting enzymeinhibitors [ACEIs] angiotensin II receptor blockers [ARBs]

6. Atopic dermatitis


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eczema 1

atopic dermatitis 1 ingestion inhalation

7. Food allergy

ingestants , , anaphylaxis

Type II hypersensitivity Antibody-mediated cytotoxic hypersensitivity

2

basement membrane antibody-dependent cell mediated cytotoxicity(ADCC)

2

hapten , hapten hapten-carriercomplex immunogenicity B lymphocyte hemolytic anemia

IgG IgM


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NK cell phagocytic cells neutrophil monocyte

, glomerular basement membrane,alveolar basement membrane basement membrane

IgG IgM 1. [agglutination]

phagocytic system reticuloendothelial system

2.

classical pathway membrane attack complex anaphylatoxin, opsonin chemotacticfactor

3. IgG C3b opsonin Fc receptor CR1 C3breceptor phagocyte phagocytosis opsonization

4. IgG Fc receptor NK-cell,neutrophil monocyte lytic enzyme phagocytosis antibody-dependent cell mediated cytotoxicity ADCC

ADCC MAC classical pathway


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[Rh- blood group] Rh- antibody D antigen D antigen Rh+ Anti-D antibody anti-Rh antibody

Hemolytic disease of the newborn due to Rh incompatibility Rh- D antigen IgG anti-D antibody Rh+

a. Rh- D Rh+ mismatch

transfusion

b. Rh+

trophoblast trophoblast [fetomaternal transplacental bleeding] D anti-D antibody anti-Rhantibody IgM primary immune response

Rh+ IgG anti-D antibody[IgG2]D [extravascular hemolysis]

fetomaternal transplacental bleeding invasiveprocedures amniocentesis, chorionic villous sampling [CVS]

antiDantibody

o Anemia


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o Jaundice indirect [unconjugated] hyperblirubinemia heme indirect

bilirubin

o Hepatosplenomegaly extravascularhemolysis

o Immune hydrops fetalis secondarytissue hypoxia [high-output heart failure]

, hydropsfetalis 50-98

o Maternal blood group

ABO Rh Rh- anti-Dantibody

o Paternal blood group Rh+

Rh+ Rh isoimmunization o Indirect Coombs test

Anti-D antibody

D Anti-D antibody D Anti-globulin antibody Coombs reagent reagent [agglutination]

anti-D antibody antibody titer Rh isoimmunization


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antibody titer 1:8

o Ultrasonography Rh isoimmunization

, , hydrops fetalis amniocentesis umbical vein blood sampling

o Amniocentesis indirect bilirubin

Rh isoimmunization

Rh fetal amniocyte PCR technique o Umbilical vein blood sampling

[fetalhemoglobin] Rhisoimmunization indirect bilirubin

Rh isoimmunization Rhogam IgG Anti-D antibody Rh- Anti-Dantibody Rhogam IgG anti-D antibody D antigen Anti-D antibody Rhogam i. 28 72 2 ii. 72

fetomaternal bleeding amniocentesis, chorionic villous sampling, spontaneousabortion 8

Rhogam anti-D antibody Rh- 99% Rhogam anti-D antibody Rh-


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D anti-D antibody

Rh incompatibility

3. Hyperacute graft rejection4. Immune thrombocytopenic purpura [ITP]5. Autoimmune diseases

2 Autoimmune hemolytic anemia [AIHA] Goodpastures syndrome

Type III hypersensitivity Immune complex-mediated hypersensitivity 3 (soluble antigen)

( Ag excess) (circulating immune complex) basement membrane


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3 IgG IgMIgG IgM

(exogenous antigen) antivenin, , , trimethoprim-sulfamethoxazole, (endogenous antigen) nucleosome, immunoglobulin autoimmune disease

neutrophil, mast cell, platelets,

3:2 (immunecomplex) basement membrane glomerular basement membrane , synovialmembrane synovial joint, choroids plexus CNS (slight antibody excess) immune complex

Arthus reaction immune complex

1. C3a, C5a C5b67 chemotactic factor neutrophil lytic enzyme

2. C3a, C4a C5a anaphylatoxin degrabulation mast cell basophil histamine, leukotrienes vasodilatation vascular permeability

3. immune complex platelet-activating factor [PAF] mast cell vasoactive amine endothelial cell immunecomplex basement membrane endothelium

4. immune complex


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immune complex complement

1. Serum sicknessSerum sickness

, , , (Hymenoptera sting) circulating immune complex


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hapten Hapten-carrier complex immune complex serum sickness-like reaction serumsickness penicillins, radiocontrast media, cephalosporins cefaclor, sulfonamides,streptomycin, thiouracils, hydantoins, dextran, hydralazine, propranolol, metronidazole

serum sickness (glonerulonephritis) serum sickness 7-14 IgG IgM secondaryimmune response 2-4 accelerated serum sickness

atopy serum sickness IgE vasoactive amine immunecomplex skin test 1 serumsickness

2. Arthus reaction

immune complex immune complex 3 tetanus toxoid


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6-8 24-48 tissue necrosis

arthus reaction bacterialspores, fungi fecal protein (pneumonitis, alveolitis)

3. Systemic lupus erythematosus (SLE)SLE prototype systemic autoimmune diseases autoantibodies immune complexes ) 3 immune complex

turbulence flow, , (butterfly rash), , , ,, ,

4. Rheumatoid arthritis

(chronic inflammatory synovitis)synovial 2, , , vasculitis, subcutaneous nodule vasculitis acute rheumaticfever rheumatoid arthritis

Fc IgG rheumatoid factor 19s IgM 7s IgM, IgG IgA rheumatoid factor rheumatoid arthritis 75-90% RFSLE, Sjgrens syndrome,Polyarteritis nodosa

5. Acute post-streptococcal glomerulonephritis [APSGN]


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GroupA streptococcus nephritogenic strain 1-4

streptococcus [molecular mimicry] immune complex 3 streptococcus alternate pathway

microscopichematuria, proteinuria,

Type IV hypersensitivity Delayed-type hypersensitivity

4

sensitizedT lymphocyte T helper 1 cell cytotoxic T cell

4 graft,

intracellular pathogen , (contactant) , , nickels

T lymphocyte TH1 TC cell, macrophage

3 1. Sensitization

antigen-presenting cell class II MHC sensitizedTH1 cell 1-2

2. Elicitation

antigen-

presenting cell sensitized T cell 2


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TH1 cell TH1 cytokine IFN- TNF-macrophage 24-72

TC cell cytotoxic Tcell specific antigenic determinant

4 1. ,

macrophage

2. specific target cell cytotoxic T cell 3.

4 activated macrophage epitheloid cell multinucleated giant cell fibroblast fibrosis

necrosis chronic granuloma

1. Allergic contact dermatitis

,

( 1000dalton) hapten allergen antigen presenting cell T lymphocyte regionallymph node T cell memory T cell memory T cell cytotoxic T cell Langerhans cell sensitized T cell 4


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2. Intracellular infection , leprosy [],

o caseous granuloma

o Mycobacterium leprae

tuberculoid leprosy CMI ,

lepromatous leprosy CMI chronic granuloma

granulomatous inflammation

3. Acute allograft rejection4. Graft-versus-host disease (GVHD)


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I IgE-mediated

(immediate)

hypersensitivity

2-30 Ag induces cross-linking of IgE bound to

mast cells with release

of vasoactive mediators

Systemic anaphylaxis,allergic

rhinitis , Asthma, Atopic

dermatitis

II Antibody-

mediated

cytotoxic

hypersensitivity

5-8 Ab directed againstcell-surface antigens

mediates cell

destruction via ADCC

or complement

Blood transfusion reactions,

Haemolytic disease of the

newborn, Autoimmune

Haemolytic anaemia

III Immune-

complex

mediated

hypersensitivity

2-8 Ag-Ab complexesdeposited at various

sites induces mast cell

degranulation via

FcgammaRIII, PMN

degranulation damages

tissue

Arthus reaction , serum sickness

acute post-streptococcal

glomerulonephritis

IV cell-mediated

(delay type)

hypersensitivity

24-72 Memory Th1 cellsrelease cytokines that

recruit and activate

macrophages, Tc cells

Contact dermatitis, Tubercular

lesions


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1. , : . 1. :

, 2543: 192-207.

2. . Leprosy. : . 2 4. : , 2545: 60-9.

3. . Acute poststreptococcal glomerulonephritis. : , , , . 3. :, 2547: 183-94.

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nd

edition. Saunder Elsevier,2006:193-208.

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324.

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thedition. New York: W.H. Freeman and

company, 2003: 361-87.

8. Gomella TL. Blood abnormalities. In: Gomella TL. Neonatology. 5 th edition USA:McGraw-Hill companies,2004: 344-9.

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