3 immunology-csbrp

Disorders of Disorders of Immunity – 3Immunity – 3

HypersensitivityHypersensitivityDr.CSBR.Prasad, Dr.CSBR.Prasad,

M.D.M.D.

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Disorders of Immune system

Hypersensitivity reactionsHypersensitivity reactions

Autoimmune diseasesAutoimmune diseases

Immunologic deficiency syndrome Immunologic deficiency syndrome – AIDS– AIDS

Amyloidosis Amyloidosis APR-2015-CSBRP


Hypersensitivity reactionsHypersensitivity reactionsDefinition:Definition:The terms The terms HypersensitivityHypersensitivity or or AllergicAllergic

statestate refer to an refer to an altered immune statealtered immune state following exposure to an antigen, following exposure to an antigen, whereby whereby subsequent contact results in subsequent contact results in tissue injury tissue injury or or a diseasea disease..

Hypersensitivity refers to undesirable (damaging and sometimes fatal) reactions produced by the normal immune system

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Protective Damaging

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Exogenous antigensExogenous antigens Dust, pollen, food, drugs, Dust, pollen, food, drugs,

microbiological agents, chemicals microbiological agents, chemicals and blood productsand blood products

Endogenous antigensEndogenous antigens Blood transfusion, graft rejection, Blood transfusion, graft rejection,

autoimmune reactionautoimmune reaction

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ClassificationClassification ( (Gell & CoombsGell & Coombs)) Type-IType-I Immediate or Immediate or AnaphylacticAnaphylactic type type Type-IIType-II Cytotoxic type Cytotoxic type Type-IIIType-III Immune complex mediated Immune complex mediated

typetype Type-IVType-IV Delayed hypersensitivity type Delayed hypersensitivity type Type-VType-V Anti-receptor type Anti-receptor type Type-VIType-VI Miscellaneous Miscellaneous

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Type I disease ( Anaphylactic type)Type I disease ( Anaphylactic type) AnaphylaxisAnaphylaxis Bronchial asthma Bronchial asthma Infantile eczema Infantile eczema Immediate drug reactionImmediate drug reaction Shock from rupture of hydatid cystShock from rupture of hydatid cyst Insect bite reactionsInsect bite reactions

Formation of Formation of IgE AbIgE Ab – release of vasoactive – release of vasoactive amines & spasmogenic substances from amines & spasmogenic substances from basophilsbasophils and and mast cellsmast cells followed by followed by recruitment by other inflammatory cellsrecruitment by other inflammatory cells

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Type II disease (cytotoxic type)Type II disease (cytotoxic type) Hemolytic transfusion reactionsHemolytic transfusion reactions HDNHDN Autoimmune Hemolytic anemiaAutoimmune Hemolytic anemia Goodpasture’s syndromeGoodpasture’s syndrome

Binding of IgG, IgM to Ag on target Binding of IgG, IgM to Ag on target cell and phagocytosis or lysis of cell and phagocytosis or lysis of target celltarget cell

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Hypersensitivity reactionsHypersensitivity reactions Type III disorder (Immune complex Type III disorder (Immune complex

disease)disease) SLESLE Acute glomerulonephritisAcute glomerulonephritis RARA PANPAN Erythema nodosumErythema nodosum

Ag-Ab complex – activate complement – Ag-Ab complex – activate complement – attract neutrophils – release of lysosomal attract neutrophils – release of lysosomal enzymes and toxic free radicalsenzymes and toxic free radicals

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Type IV disorder (Cell Type IV disorder (Cell mediated/delayed mediated/delayed hypersensitivity)hypersensitivity) Caseous necrosis in TuberculosisCaseous necrosis in Tuberculosis Leprosy neuritisLeprosy neuritis Contact dermatitisContact dermatitis

Sensitized T lymphocytes – cell Sensitized T lymphocytes – cell mediated cytotoxicitymediated cytotoxicity

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Type V disorder (Type V disorder (Anti-receptor Anti-receptor typetype)) Grave’s diseaseGrave’s disease Myasthenia gravisMyasthenia gravis Insulin resistant diabetesInsulin resistant diabetes

Formed antibodies bind with receptors.Formed antibodies bind with receptors.Results can be excessive Results can be excessive activationactivation or or

blockadeblockade

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Type VI disorder (Miscellaneous)Type VI disorder (Miscellaneous)They are due to pure activation of They are due to pure activation of

alternate pathway of compelmentalternate pathway of compelment Gram negative endotoxic shockGram negative endotoxic shock PNHPNH

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Type I HypersensitivityType I Hypersensitivity ( Anaphylactic type) ( Anaphylactic type)

Rapidly developing Rapidly developing immunological reactionimmunological reaction

Systemic reactionSystemic reaction – IV injection – IV injection of antigenof antigen

Local reactionLocal reaction – Skin / GIT / – Skin / GIT / Respiratory / ConjunctivalRespiratory / Conjunctival

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Reaction occurs in Reaction occurs in 2 phases2 phases Intial responseIntial response – occurs within 5-30 min – occurs within 5-30 min

after exposure to allergen & last for 60 after exposure to allergen & last for 60 min.min.Vasodilatation, vascular leakage, smooth Vasodilatation, vascular leakage, smooth muscle spasm/ glandular secretionmuscle spasm/ glandular secretion

Late phase responseLate phase response - Occurs after 2 – 8 - Occurs after 2 – 8 hours without additional exposure to Ag hours without additional exposure to Ag and last for daysand last for days

Infiltration by eosinophils, neutrophils, Infiltration by eosinophils, neutrophils, basophils, monocytes and CD4 T cellbasophils, monocytes and CD4 T cell

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Mast cellsMast cellsNear blood vessels, nerves and in Near blood vessels, nerves and in

subepithelial sitessubepithelial sites Membrane bound granules Membrane bound granules

containing biologically active containing biologically active mediators mediators

Metachromatic granulesMetachromatic granules Activation by cross linking of IgE Fc Activation by cross linking of IgE Fc

receptor, C5a, C3a, cytokines (IL- receptor, C5a, C3a, cytokines (IL- 8), drugs (codeine, morphine)8), drugs (codeine, morphine)

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Figure 6-12 Pathogenesis of immediate (type I) hypersensitivity reaction.

The late-phase reaction is dominated by leukocyte infiltration and tissue injury. TH2, T-helper type 2 CD4 cells.

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Figure 15-10 A simplified scheme of the system of type 1 helper T (TH1) and type 2 helper (TH2) cells.

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Primary mediatorsPrimary mediators Biologenic aminesBiologenic amines::

Histamine – bronchial SM contractor, ↑ vascular Histamine – bronchial SM contractor, ↑ vascular permeability, ↑ secretionpermeability, ↑ secretion

Adenosine – Bronchoconstriction, Platelet Adenosine – Bronchoconstriction, Platelet aggregationaggregation

Chemotactic mediatorsChemotactic mediators – Eosinophils, – Eosinophils, NeutrophilsNeutrophils

EnzymesEnzymes – Proteases, Acid hydrolases – Proteases, Acid hydrolases Proteoglycans Proteoglycans – Heparin, chondroitin – Heparin, chondroitin

sulfatesulfateMajor site of action of HISTAMINE: Venules

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Secondary MediatorsSecondary Mediators LeukotriensLeukotriens:

C4 & D4 – vasoactive and spasmogenicC4 & D4 – vasoactive and spasmogenic B4- chemotactic for PMN, EØ, MonocytesB4- chemotactic for PMN, EØ, Monocytes

Prostoglandins D2Prostoglandins D2 – Bronchospasm, – Bronchospasm, ↑secretion↑secretion

PAFPAF – Pl. aggregation, release of – Pl. aggregation, release of histaminehistamine

CytokinesCytokines – Recruit & activate – Recruit & activate inflammatory cellsinflammatory cells

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Figure 6-13 Activation of mast cells in immediate hypersensitivity and release of their mediators. ECF, eosinophil chemotactic factor; NCF, neutrophil chemotactic factor; PAF, platelet-activating factor.

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Immediate reactionImmediate reaction HistamineHistamine LeukotriensLeukotriens

Late phase reactionLate phase reaction PAFPAF TNF -αTNF -α CytokinesCytokinesEosinophilsEosinophils – major basic protein , EØ cationic – major basic protein , EØ cationic

protein, leukotriens C4, PAFprotein, leukotriens C4, PAFDirectly activate Mast cells to release Directly activate Mast cells to release

mediatorsmediators

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Systemic AnaphylaxisSystemic Anaphylaxis Antisera, Hormones, Enzymes, DrugsAntisera, Hormones, Enzymes, Drugs Itching, erythema, respiratory Itching, erythema, respiratory

distress, laryngeal edema, deathdistress, laryngeal edema, death Local AnaphylaxisLocal Anaphylaxis

Atopic allergy – Atopic allergy – Genetically Genetically determineddetermined ~10% of the population ~10% of the population

predisposition to develop reaction to predisposition to develop reaction to inhaled / ingested allergensinhaled / ingested allergens

Urticaria, angioedema, allergic Urticaria, angioedema, allergic rhinitis, asthmarhinitis, asthma

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Type II HypersensitivityType II Hypersensitivity ( (Cytotoxic typeCytotoxic type))

Mediated by Abs to Mediated by Abs to cell surface Agscell surface Ags and components of and components of extracellular extracellular matrixmatrix

3 mechanisms3 mechanisms1.1. Complement dependent reactionComplement dependent reaction2.2. Antibody dependent cell mediated Antibody dependent cell mediated

cytotoxicity (ADCC)cytotoxicity (ADCC)3.3. Antibody mediated cellular Antibody mediated cellular

dysfunctiondysfunction

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Complement dependent Complement dependent reactionreaction

Direct lysis – Direct lysis – Membrane Attack Complex – C5-9Membrane Attack Complex – C5-9

OpsonizationOpsonization Attachment of Ab/C3b fragment to Attachment of Ab/C3b fragment to

cell surfacecell surface

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Opsonisation & cell lysisOpsonisation & cell lysis

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Complement mediated Complement mediated lysis lysis

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Complement dependent Complement dependent reactionreaction

Transfusion reactionsTransfusion reactions Erythrhroblastosis fetalisErythrhroblastosis fetalis Autoimmune Hemolytic anemiaAutoimmune Hemolytic anemia Pemphigus vulgaris – Ab against Pemphigus vulgaris – Ab against

desmosomesdesmosomes

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Antibody dependent cell Antibody dependent cell mediated cytotoxicity mediated cytotoxicity

(ADCC)(ADCC) Target cells coated with IgG Ab are Target cells coated with IgG Ab are

killed by nonsensitized cells that killed by nonsensitized cells that have Fc receptorhave Fc receptor

Cell lysis without phagocytosisCell lysis without phagocytosis Mediated by monocytes, Mediated by monocytes,

neutrophils, eosinophils & NK cellsneutrophils, eosinophils & NK cells Parasite, tumor cell, graft rejectionParasite, tumor cell, graft rejection

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ADCC – apoptosis by NK cellsADCC – apoptosis by NK cells

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1.1. What is the % of Rh negativity?What is the % of Rh negativity?2.2. Which HDN is more common?Which HDN is more common?3.3. Which HDN is more severe?Which HDN is more severe?4.4. What is RhoGAM?What is RhoGAM?5.5. How do you assess transplacental bleed?How do you assess transplacental bleed?6.6. How do you assess anemia in a fetus?How do you assess anemia in a fetus?7.7. What are the other causes for Hydrops What are the other causes for Hydrops

fetalis?fetalis?

Type II HypersensitivityType II Hypersensitivity ( (Cytotoxic typeCytotoxic type))

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Antibody mediated cellular Antibody mediated cellular dysfunctiondysfunction

Myasthenia Gravis Myasthenia Gravis – Ab react – Ab react with acetochyline receptor in the with acetochyline receptor in the motor end plate of skeletal motor end plate of skeletal muscle – muscle weaknessmuscle – muscle weakness

Graves diseaseGraves disease – Ab against TSH – Ab against TSH receptor on thyroid epithelial receptor on thyroid epithelial cells - Hyperthyroidismcells - Hyperthyroidism

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Type II HypersensitivityType II Hypersensitivity (cytotoxic type) (cytotoxic type)

Good pasture syndrome – Good pasture syndrome – Type IV collagen of BM of glomeruli Type IV collagen of BM of glomeruli

and lung alveoliand lung alveoli Bullous pemphigoidBullous pemphigoid

Epithelial BM proteinEpithelial BM protein Pernicious anemiaPernicious anemia

Intrinsic factor and gastric parietal cellIntrinsic factor and gastric parietal cell Acute rheumatic feverAcute rheumatic fever

Ab against streptococus cross react Ab against streptococus cross react with heartwith heart

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Goodpasture Syndrome

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Bullous Bullous pemphigoidpemphigoid

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Type III HypersensitivityType III Hypersensitivity((Immune Complex Immune Complex

MediatedMediated)) Antigen – Antibody complexes Antigen – Antibody complexes

produces tissue damage by produces tissue damage by eliciting inflammation at the site eliciting inflammation at the site of depositionof deposition

Circulating immune complexesCirculating immune complexes Deposited in vessel wallDeposited in vessel wall

In Situ immune complexesIn Situ immune complexes Extrasvascular placesExtrasvascular places

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Type III HypersensitivityType III Hypersensitivity(Immune Complex (Immune Complex

Mediated)Mediated)Two types of AntigenTwo types of Antigen Exogenous AgExogenous Ag

Foreign protein, bacteria, virusForeign protein, bacteria, virus Endogenous AgEndogenous Ag

Circulating Ag in bloodCirculating Ag in blood Nuclear AgNuclear Ag

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Systemic immune Systemic immune complex diseasecomplex disease

Acute serum sickness – injection Acute serum sickness – injection of horse serumof horse serum

3 phase3 phase Immune complex formationImmune complex formation Immune complex depositionImmune complex deposition Immune complex mediated Immune complex mediated

inflammationinflammation

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Mediated)Mediated) Factors affecting out come of immune Factors affecting out come of immune

complexcomplex Size of immune complexSize of immune complex Functional status of phagocyte systemFunctional status of phagocyte system

Charge of immune complex, affinity Charge of immune complex, affinity of Ag to various tissue component of Ag to various tissue component and hemodynamic factor influences and hemodynamic factor influences tissue deposition of immune complextissue deposition of immune complex

Glomeruli, joints, skin, heart, blood Glomeruli, joints, skin, heart, blood vesselvessel

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Mediated)Mediated) Immune complex deposited in tissue Immune complex deposited in tissue

elicit acute inflammatory reactionelicit acute inflammatory reaction Fever, Fever, urticariaurticaria, , arthralgiaarthralgia, lymph , lymph

node enlargement and node enlargement and proteinuriaproteinuria Activation of complement cascadeActivation of complement cascade – –

C3a, C5aC3a, C5a Activation of neutrophil & Activation of neutrophil &

macrophages through their Fc macrophages through their Fc receptorreceptor

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Mediated)Mediated) Release of proinflammatory Release of proinflammatory

mediatorsmediators PG, vasodilator peptides, chemotactic PG, vasodilator peptides, chemotactic

substances, lysosomal enzymes and substances, lysosomal enzymes and oxygen free radicals – tissue damageoxygen free radicals – tissue damage

Immune complex – platelet Immune complex – platelet aggregation & Hageman factor aggregation & Hageman factor activation – microthrombi formationactivation – microthrombi formation

Vasulitis / GlomerulonephritisVasulitis / Glomerulonephritis

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Systemic immune Systemic immune complex diseasecomplex disease

MorphologyMorphology Acute necrotizing vasculitisAcute necrotizing vasculitis GlomerulonephritisGlomerulonephritis – –

SLE, Acute poststreptococcal GNSLE, Acute poststreptococcal GN Collagen disorderCollagen disorder

Rheumatoid arthritis, Rheumatoid arthritis, polyarteritis nodosa, polyarteritis nodosa,

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Acute necrotizing Acute necrotizing vasculitisvasculitis

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Local immune complex Local immune complex diseasedisease

((Arthus reactionArthus reaction)) Localized area of tissue necrosis Localized area of tissue necrosis

resulting from acute immune resulting from acute immune complex vasculitis usually in the complex vasculitis usually in the skinskin

Arthus lesion develop over few Arthus lesion develop over few hours & reaches peak 4-10 hours hours & reaches peak 4-10 hours after injectionafter injection

M/S – fibrinoid necrosis of vesselM/S – fibrinoid necrosis of vessel

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Type IV HypersensitivityType IV Hypersensitivity(Cell mediated)(Cell mediated)

Intiated by specifically sensitized T Intiated by specifically sensitized T lymphocyteslymphocytes

Immunological reaction to M. Tuberculosis, Immunological reaction to M. Tuberculosis, virus, fungi, protozoa & parasitevirus, fungi, protozoa & parasite

Contact dermatitisContact dermatitis Graft rejectionGraft rejection

Two typesTwo types1.1. Classic delayed type hypersensitivity Classic delayed type hypersensitivity

reaction – mediated by CD4 T cellreaction – mediated by CD4 T cell2.2. Direct cell cytotoxicity - Mediated by CD8 Direct cell cytotoxicity - Mediated by CD8

T cellT cell

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Classic delayed type Classic delayed type hypersensitivityhypersensitivity

Tuberculin reactionTuberculin reaction Protein lipopolysaccharide component Protein lipopolysaccharide component

of tubercle bacilliof tubercle bacilli Reddening & induration of site – 8-12 Reddening & induration of site – 8-12

hourshours Peak in 24 – 72 hoursPeak in 24 – 72 hours

M/SM/S Perivascular mononuclear cell Perivascular mononuclear cell

infiltrationinfiltration Edema & fibrin depositionEdema & fibrin deposition

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Tuberculin testTuberculin test

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Persistent / nondegradable Ag – Persistent / nondegradable Ag – lymphocytes are replaced by lymphocytes are replaced by macrophages over 2 -3 weeks -- macrophages over 2 -3 weeks -- epithelioid cellsepithelioid cells

GranulomaGranuloma – microscopic – microscopic aggregate of epithelioid cells aggregate of epithelioid cells surrounded by collar of surrounded by collar of lymphocyteslymphocytes

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CytokinesCytokines IL-12IL-12 IFN γ IFN γ IL-2IL-2 TNFTNF

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Figure 6-21Schematic illustration of the events that give rise to the formation of granulomas in cell-mediated (type IV) hypersensitivity reactions. Note the role played by T cell-derived cytokines.

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CytokinesCytokines IL-12IL-12

Derived from macrophageDerived from macrophage Differentiation of CD4+ helper cell Differentiation of CD4+ helper cell

to Tto THH1 cell1 cell Induces IFN γ secreation by T cell & Induces IFN γ secreation by T cell &

NK cellNK cell

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Interferon – gamma (IFN γ )Interferon – gamma (IFN γ ) Important mediator of delayed Important mediator of delayed

hypersensitivityhypersensitivity Powerful activator of macrophagesPowerful activator of macrophages Stimulate the secretion of IL – 12Stimulate the secretion of IL – 12 Express more class II molecule on the Express more class II molecule on the

surfacesurface ↑ ↑ capacity to kill micro organism/tumour capacity to kill micro organism/tumour

cellcell Secretes PDGF & TGF – β -- stimulate Secretes PDGF & TGF – β -- stimulate

fibroblast proliferation - fibrosisfibroblast proliferation - fibrosis

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IL – 2IL – 2 Autocrine & paracrine proliferation of T Autocrine & paracrine proliferation of T

cellscells TNF – α and lymphotoxinTNF – α and lymphotoxin

Act on endothelial cellsAct on endothelial cells ↑ ↑ secretion of prostacyclin – vasodilatationsecretion of prostacyclin – vasodilatation ↑ ↑ expression of E selectinexpression of E selectin Secretion of IL-8Secretion of IL-8Overall effect is extravasation & Overall effect is extravasation &

accumulation of lymphocyte and monocyte accumulation of lymphocyte and monocyte at the site of reactionat the site of reaction

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Type VType V

Receptor type of Antibodies

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Type V HypersensitivityType V HypersensitivityIgG antibodies against cell-surface receptors disrupt the normal functions of the receptor.

By causing :

- uncontrolled activation or

- by blocking receptor function.

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E N DE N D

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