hypersensituvty 3 & 4

8/6/2019 hypersensituvty 3 & 4

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HYPERSENSITIVITY REACTIONS HYPERSENSITIVITY REACTIONS TYPE III & IV TYPE III & IV

- Benita Nancy Reni.M

5-12h, Type III (Arthus Rx) 24h-, Type IV-15¶, Type I



TypeType III III HypersensitivityHypersensitivity

immune complex mediated Hypersensitivity.immune complex mediated Hypersensitivity.

Large amounts of immune complexes lead toLarge amounts of immune complexes lead to tissuetissue--damaging Typedamaging Type III III

Hypersensitivity.Hypersensitivity.

A g A g-- Ab Ab complexes deposition in various tissuescomplexes deposition in various tissues

-- induce complement activationinduce complement activation

-- massive infiltration of massive infiltration of neutrophilsneutrophils -- inflammatory responseinflammatory response

Magnitude of the reaction depends onMagnitude of the reaction depends on

Quantity of immune complexes.Quantity of immune complexes.

distribution within the body.distribution within the body.



Based on immune complex deposition,Based on immune complex deposition,

Localized reaction Localized reaction

complex deposition very near to the site of the antigencomplex deposition very near to the site of the antigen

entry.entry.

Generalized reaction Generalized reaction

when the immune complexes formed in bloodwhen the immune complexes formed in blood



IIstst described by a French scientistdescribed by a French scientist MAURICE ARTHUS MAURICE ARTHUS in 1903.in 1903.

And the story is. And the story is.

He immunized rabbits with horse serum byHe immunized rabbits with horse serum by repeatedrepeated intradermalintradermal

Injection.Injection.

A n A n erythematouserythematous & edematous& edematous reactionreaction

(reaching a peak at 3(reaching a peak at 3--8 hrs8 hrs then, resolved)then, resolved)

characterizedby an intense infiltration withcharacterized

by an intense infiltration with neutrophilsneutrophils..

Arthus Arthus reactionreaction

prototype of localized Typeprototype of localized Type IIIIII immune complex reactions.immune complex reactions.



Mechanism behindMechanism behind

IMMUNE COMPLEX DEPOSITION ON BASAL MEMBRANE

ENDOTHELIAL CELLBASAL MEMBRANE

COMPLEMENT ACTIVATION

ATTRACTION OF PHAGOCYTES

HAEMORRHAGE & THROMBOSIS: TISSUE DAMAGE & DYSFUNCTION



Immune complexesImmune complexes

A ctivates the complement systems array of effector molecules. A ctivates the complement systems array of effector molecules.

C3a, C4a, C5a

Anaphylatoxins.

Cause localized mast cell

degranulation.

Consequent increase inlocal vascular permeability.

C3a, C5a, C5b67

� Chemotactic factors

for NEUTROPHILS.

Accumulate in large

numbers in large

numbers at the site of

immune complexdeposition.

C3b complement ± opsonin,

Coating immune complexes

Neutrophil binds to a C3b-

coated immune complex by

means of specific type 1

complement receptor.

� As the complex isdeposited on the basement

membrane surface,

Phagocytosis is impeded.

� Lytic enzymes are released

Further activation of membrane attack mechanism.

Activation of complement ± also, induce aggregation

of platelets ± release of clotting factors ± formation of

microthrombi.



During complement activationDuring complement activation..



Localized reactionsLocalized reactions A rthus reaction A rthus reaction Severity of the reaction can vary from mild swelling & rednessSeverity of the reaction can vary from mild swelling & redness

to tissue necrosis.to tissue necrosis.

A fter an insect bite, a sensitive individual may have a rapid, localized type 1 A fter an insect bite, a sensitive individual may have a rapid, localized type 1reaction at the site.reaction at the site.

44--8 hrs later8 hrs later, A rthus reaction with pronounced, A rthus reaction with pronounced erythema & edemaerythema & edema resultsresultsinin localized tissue & vascular damagelocalized tissue & vascular damage

Reactions to inhaled antigens Reactions to inhaled antigens Intrapulmonary Arthus Intrapulmonary Arthus type type reaction.reaction.

Induced by bacterial spores, fungi, dried feccal proteinsInduced by bacterial spores, fungi, dried feccal proteins causecause pneumonitis / alveolitispneumonitis / alveolitis..

ReactionsReactions known by common namesknown by common names reflecting the sourcereflecting the sourceof the antigen.of the antigen.

Farmers lung Farmers lung inhalation of thermophilic actinomycetesinhalation of thermophilic actinomycetesfrom moldy hay.from moldy hay.

Pigeon fanciers disease Pigeon fanciers disease -- inhalation of a serum protein ininhalation of a serum protein indust derived from dried pigeon feces.dust derived from dried pigeon feces.

OCCUPATIONAL

DISEASES



eneralized reactionsGeneralized reactionsSERUM SICKNESS..SERUM SICKNESS..

Develop after injection of large quantities of Develop after injection of large quantities of

foreign serum. (Eg: passive immunization withforeign serum. (Eg: passive immunization withhyperimmune serumhyperimmune serum

qq

Recipient produces abs to ag in serumRecipient produces abs to ag in serumqq

IC formationIC formationqq

Spreading & deposition of IC Throughout theSpreading & deposition of IC Throughout thebody. (Blood vessels, skin, kidney, joints)body. (Blood vessels, skin, kidney, joints)

Sites of deposition depends on,..Sites of deposition depends on,.. Quantity of IC Quantity of IC Overall size of ICOverall size of IC

Sites of deposition vary, but accumulate in Sites of deposition vary, but accumulate in tissues where filtration occurs.tissues where filtration occurs.

Glomerulonephritis (kidney).Glomerulonephritis (kidney).

V asculitis (arteries).V asculitis (arteries).

Arthritis (synovial joints). Arthritis (synovial joints).

Symptoms include.. Fever, weakness, Symptoms include.. Fever, weakness,

generalized vasculitis with edema & generalized vasculitis with edema &

erythema, lymphoadenopathy, arthritis & erythema, lymphoadenopathy, arthritis &

GlomerulonephritisGlomerulonephritis

AUTOIMMUNE DISEASES AUTOIMMUNE DISEASES

SYSTEMIC LUPUS ERYTHEMATOSUS.SYSTEMIC LUPUS ERYTHEMATOSUS.

Complexes of DNA & antiComplexes of DNA & anti--DNA antibodies DNA antibodies

accumulate in synovial membraneaccumulate in synovial membrane

causing arthritic symptoms.causing arthritic symptoms.

/ accumulate on the basement / accumulate on the basement

membrane of kidney membrane of kidney causing causing

progressive kidney damage.progressive kidney damage.

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

IgM autoantibody IgM autoantibody Fc portion of normal IgG Fc portion of normal IgG

cplxs cplxs causing inflammation of joints & the causing inflammation of joints & the

destruction.destruction.

GOODP ASTURES SYNDROMEGOODP ASTURES SYNDROME

Ab Ab directly binds to basement membrane in directly binds to basement membrane in

the lung & kidney the lung & kidney activates complement activates complement

accumulation of neutrophils accumulation of neutrophils release of release of

degradative enzymes degradative enzymes membrane damage.membrane damage.

Pulmonary heamorrage & glomerulonephritisPulmonary heamorrage & glomerulonephritis



Drug reactionsDrug reactions

A llergies to penicillin & sulfonamides A llergies to penicillin & sulfonamides..

Infectious diseasesInfectious diseases

Poststreptococcal glomerulonephritisPoststreptococcal glomerulonephritis ::

develops when circulating complexes of antibody and streptococcal antigens aredevelops when circulating complexes of antibody and streptococcal antigens are

deposited in the kidney & damage the glomeruli.deposited in the kidney & damage the glomeruli.

MeningitisMeningitisHepatitisHepatitisMononucleosisMononucleosisMalariaMalaria

TrypanosomiasisTrypanosomiasis

Deposition of IgG-immune complexes in glomeruli



Clinical historyClinical history

Biopsy to show:Biopsy to show:

Neutrophil accumulation.Neutrophil accumulation.

Deposition of complement.Deposition of complement.

Deposition of IgG & IgM.Deposition of IgG & IgM.

Determination of ic in serumDetermination of ic in serum

Decreased total serumDecreased total serum

complement complement

Presence of serum activationPresence of serum activation

products: C3a, C5aproducts: C3a, C5a

CORTICOSTEROIDSCORTICOSTEROIDS

inhibitors of inflammation &inhibitors of inflammation &

immunosuppressiveimmunosuppressive

Sodium cromoglycateSodium cromoglycate

HeparinHeparin

SalicylatesSalicylates effective platelet effective platelet

stabilizer & potent antistabilizer & potent anti--

inflammatory agent inflammatory agent

Diagnosis of Type III reactions Treatment of Type III reactions



TYPE IVTYPE IV HYPERSENSITIVITYHYPERSENSITIVITY

Delayed type hypersensitivity.Delayed type hypersensitivity.

TT--Cell mediatd hypersensitivity.Cell mediatd hypersensitivity.

WhenWhen activated Tactivated THH CellsCells encounter certain types of antigensencounter certain types of antigens secrete cytokinessecrete cytokines

induce a local inflammatory reaction.induce a local inflammatory reaction.

Characterized byCharacterized by erythema & indurationerythema & induration appears only after several hrs ( hence,appears only after several hrs ( hence,

the term delayed)the term delayed) reaches maximum at 24reaches maximum at 24--48 hrs.48 hrs.

Histologically, Characterized by large influx of nonspecific inflammatory cells, inHistologically, Characterized by large influx of nonspecific inflammatory cells, in

patricular,patricular, macrophagesmacrophages..

TTHH Cells involving in this reaction are calledCells involving in this reaction are called TTDTH DTH cells.cells.

CD8CD8++

cells also shown to induce a DTH response.cells also shown to induce a DTH response.

Response playsResponse plays important role in defense against intracellular pathogens & important role in defense against intracellular pathogens &

contact antigenscontact antigens an example of an example of cellcell--mediated immunity mediated immunity ..



11st st described in 1890 by ROBERT KOCHdescribed in 1890 by ROBERT KOCH

He observed that individuals infected withHe observed that individuals infected with Mycobact erium tuberculosis Mycobact erium tuberculosis developeddeveloped

a localized inflammatory responsea localized inflammatory response

When injected intradermally with a filtrate derived from a mycobacterial culture.When injected intradermally with a filtrate derived from a mycobacterial culture.

He called this localized skin reaction aHe called this localized skin reaction a tuberculin reaction. tuberculin reaction.

Later, its name was changed toLater, its name was changed to delayed type / type IV hypersensitivitydelayed type / type IV hypersensitivity..

A s it became apparent that a variety of antigens could induce this response. A s it became apparent that a variety of antigens could induce this response.

The hallmarks of a type IV reaction areThe hallmarks of a type IV reaction are

the delay in time required.the delay in time required.

the recruitment of macrophages.the recruitment of macrophages.




Sensitization phaseSensitization phase11-- 2 weeks after initial2 weeks after initialcontactcontact

Primary contact with an antigenPrimary contact with an antigen

TTHH Cells activated & clonallyCells activated & clonallyexpanded..expanded..

A g enters thru skin A g enters thru skin

Langerhan cells ( A PC) pick up &Langerhan cells ( A PC) pick up &

transport it to regional lymphtransport it to regional lymphnodes.nodes.

TTHH Cells are activated & clonallyCells are activated & clonallyexpanded..expanded..

Effector phaseEffector phaseafteraftersubsequent exposure to an ag..subsequent exposure to an ag..

subsequent exposure of sensitizedsubsequent exposure of sensitizedTH1 cells to antigenTH1 cells to antigen

induce TH1 cells tosecrete ainduce TH1 cells tosecrete avariety of cytokines &variety of cytokines &chemokineschemokines

attract & activate macrophagesattract & activate macrophages

& other nonspecific& other nonspecificinflammatory cells.inflammatory cells.



Activated macrophages Activated macrophages

exhibit exhibit sed levels of phagocytosis sed levels of phagocytosis

A n A n sed ability to kill microorganismssed ability to kill microorganisms

thru various cytotoxic mediators.thru various cytotoxic mediators. expressexpress sed levels of class II MHCsed levels of class II MHC

molecules and cellmolecules and cell--adhesion moleculesadhesion molecules --

function as APCsfunction as APCs -- thusthus perpetuating perpetuating

the DTH response.the DTH response.

The heightened phagocytic activity & theThe heightened phagocytic activity & thebuildup of lytic enzymes from macrophagesbuildup of lytic enzymes from macrophages

lead to nonspecific destruction of cells,lead to nonspecific destruction of cells,

thus of the intracellular pathogen.thus of the intracellular pathogen.

A prolonged DTH response A prolonged DTH response -- destructive to thedestructive to thehost host granulomatous reaction.granulomatous reaction.

Characteristics of the reactionCharacteristics of the reaction

A DTH response A DTH response -- does not become does not become

apparent until an average of 24 h after apparent until an average of 24 h after

the 2the 2ndnd contact with the antigen.contact with the antigen.

the response generally peaks 48the response generally peaks 48 72 h 72 h

after second contact.after second contact.

The delayed onset of this response The delayed onset of this response

reflects the time required for the reflects the time required for the

cytokines to induce localized influxes of cytokines to induce localized influxes of

macrophages and their activation.macrophages and their activation.

When DTH response is fully developed, When DTH response is fully developed,

only about 5% of the participating cells only about 5% of the participating cells

are antigenare antigen--specific TH1 cells;specific TH1 cells;

the remainder are macrophages and the remainder are macrophages and

other nonspecific cells.other nonspecific cells.



Lymphokine secretion in DTHLymphokine secretion in DTH ILIL--3 & GM3 & GM--CSFCSF : induce localized hematopoiesis of the granulocyte: induce localized hematopoiesis of the granulocyte--monocytesmonocytes

lineage.lineage.

IFNIFN-- & TNF& TNF-- ((together with macrophage((together with macrophage--derived TNFderived TNF-- and ILand IL--1)1) : act on: act on

nearby endothelial cells, inducing a number of changes that facilitates the extravasionnearby endothelial cells, inducing a number of changes that facilitates the extravasion

of monocytes & other nonspecific inflammatory cellsof monocytes & other nonspecific inflammatory cells

Monocyte chemotactic & activating factor (MCAF):Monocyte chemotactic & activating factor (MCAF):A s the monocytes enter the

A s the monocytes enter the

tissuestissues differentiates into macrophages, chemotactically drawn to the site of differentiates into macrophages, chemotactically drawn to the site of

antigen by this.antigen by this.

Macrophage inhibiting factor (MIF) :Macrophage inhibiting factor (MIF) : keeps the macrophages fromkeeps the macrophages from

leaving site.leaving site.

InterferonInterferon-- and membrane bound TNFand membrane bound TNF-- (produced by TH1 cells):(produced by TH1 cells): activatesactivates

macrophages.macrophages.

Interleukin 2 (ILInterleukin 2 (IL--2) :2) : activates T helper and cytotoxic T cells andactivates T helper and cytotoxic T cells and

induces their proliferation.induces their proliferation.



Granulomatous HypersensitivityGranulomatous Hypersensitivity

clinically most importantclinically most important

Results from failed killing of an Results from failed killing of an intracellular microorganism by intracellular microorganism by

macrophages.macrophages.

continuous activation of macrophages continuous activation of macrophages

induces the macrophages to adhere closely induces the macrophages to adhere closely

to one another, assuming an epithelioid to one another, assuming an epithelioid shape shape -- Characteristic cell derived from Characteristic cell derived from

multiple macrophagesmultiple macrophages

sometimes fusing to form multinucleated sometimes fusing to form multinucleated

giant cells giant cells -- displace the normal tissue.displace the normal tissue.

release high concentrations of lytic release high concentrations of lytic

enzymesenzymes-- destroy surrounding tissue destroy surrounding tissue -- can can

damage blood vessels and lead to extensive damage blood vessels and lead to extensive

tissue necrosis.tissue necrosis.

Requires at least 14

days to observe Requires at least 14

days to observe experimentally.experimentally.

Tubercules found in the tissues of patients with

TB are granulomas formed around the slow-

growing Mycobacteria through influence of DTH

T cells



Contact hypersensitivityContact hypersensitivity

Target organ is skin.Target organ is skin.

Inflammatory response Inflammatory response result of sensitizing substances on the surface of skin.result of sensitizing substances on the surface of skin.

For eg: Formaldehyde, trinitrophenol, nickel, turpentine, active agents in various For eg: Formaldehyde, trinitrophenol, nickel, turpentine, active agents in various

cosmetics & hair dyes, poison oak & poison ivy.cosmetics & hair dyes, poison oak & poison ivy.

Most of these substances Most of these substances small molecules that can complex with skin proteins.( in small molecules that can complex with skin proteins.( in

poison oak, pentadecacatechol complexes with skin protein)poison oak, pentadecacatechol complexes with skin protein)

The complex is internalized by Langerhans cells The complex is internalized by Langerhans cells processed & presented together processed & presented together

with class II MHC molecules with class II MHC molecules activation of sensitized Tactivation of sensitized THH1 Cells.1 Cells.

Subsequent exposure Subsequent exposure elicit activation of Telicit activation of THH1 Cells& induce cytokine production.1 Cells& induce cytokine production.

4848--72 hrs after 272 hrs after 2ndnd

exposure, accumulation of macrophages exposure, accumulation of macrophages release of lytic enzymes.release of lytic enzymes. Reaction is characterized by..Reaction is characterized by.. mononuclear cell infilteration.mononuclear cell infilteration.

edema & microvesicle formation.edema & microvesicle formation.

Addition pathogenic component in humans Addition pathogenic component in humans

Seperation of epidermal cells.Seperation of epidermal cells.

Spongiosis.Spongiosis.

Blister formation.Blister formation.

Blister



Patch test to assess Contact hypersensitivityPatch test to assess Contact hypersensitivity

The suspected allergen is applied over the skin.The suspected allergen is applied over the skin.

The appearance of an area of of induration & erythemaThe appearance of an area of of induration & erythema indicates sensitivity.indicates sensitivity.

NICKEL ALLERG YNICKEL ALLERG Y



Jones Mote reactions.Jones Mote reactions.

A n unusual form of DTH. A n unusual form of DTH.

Observed in individuals following repeatedObserved in individuals following repeated

intradermal injections of antigens.intradermal injections of antigens.

The response is delayed in onset (about 24The response is delayed in onset (about 24

hrs)hrs)

Consists entirely of Consists entirely of erythemaerythema,, without without induration.induration.

It was found that theIt was found that the erythema erythema result of result of

infiltration of basophil.infiltration of basophil.

CBH may have an important role in certainCBH may have an important role in certain

forms of immunity against forms of immunity against parasites, bloodparasites, blood--

feeding insectsfeeding insects

Basophil infiltrateBasophil infiltrate also, found in cases of also, found in cases of

contact dermatitis (poison ivy).contact dermatitis (poison ivy).

Re jection of renal grafts.Re jection of renal grafts.

In some forms of con junctivitis.In some forms of con junctivitis.

A llografts in the reciepient A llografts in the reciepient

Initially be accepted & becomeInitially be accepted & becomevascularizedvascularized

Rejection reaction, bcaz of cellRejection reaction, bcaz of cell--

mediated hypersensitivity against mediated hypersensitivity against alloantigens.alloantigens.

CUTANEOUS BASOPHIL HYPERSENSITIVITY« ALLOGRAFT REJECTION«



Tuberculin hypersensitivity..Tuberculin hypersensitivity..

Tuberculin skin test Tuberculin skin test When purified tuberculin is injectedWhen purified tuberculin is injected

into the skininto the skin

memory DTH cells attract memory DTH cells attract

macrophages and granulocytes andmacrophages and granulocytes andcausecause

induration and erythema.induration and erythema.

Positive test indicates exposure toPositive test indicates exposure to M.M.

TuberculosisTuberculosis and production of Ab.and production of Ab.

But, Positive test does not allow one toBut, Positive test does not allow one to

conclude whether the exposure wasconclude whether the exposure was

pathogenic form of pathogenic form of M. tuberculosisM. tuberculosis / to / to

a vaccine form.a vaccine form.

Strongly positive ³ Mantoux test ³ in a patient with

active tuberculosis. Intradermal injection of M.

tuberculosis antigen has induced a florid type IV

hypersensitivity reaction with some blistering.



Treatment of serious TYPE IV reactions..Treatment of serious TYPE IV reactions..

Treatment based on inhibition of Treatment based on inhibition of

phagocyte accumulation.phagocyte accumulation.

release of highly reactive oxidants andrelease of highly reactive oxidants and

proteolytic enzymes.proteolytic enzymes. Proliferation of cd4+ & cd8+ t Proliferation of cd4+ & cd8+ t--lymphocytes.lymphocytes.

CORTICOSTEROIDS, CYTOTOXIC DRUGSCORTICOSTEROIDS, CYTOTOXIC DRUGS



THANK YOU««..

hypersensituvty 3 & 4

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