Autoimunitas 11

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AUTOIMUNITASAUTOIMUNITAS

Neni Susilaningsih

Fakultas Kedokteran Universitas Diponegoro

Semarang11

AUTOIMUNITASAUTOIMUNITAS

Autoimunitas merupakan keadaan hilangnya Autoimunitas merupakan keadaan hilangnya selfself toleranstolerans sehingga terjadi reaksi imunsehingga terjadi reaksi imunselfself--toleranstolerans sehingga terjadi reaksi imun sehingga terjadi reaksi imun terhadap antigen jaringan sendiri terhadap antigen jaringan sendiri kerusakan jaringan.kerusakan jaringan.

Toleransi terhadap selfToleransi terhadap self--Ag dapat terjadi di Ag dapat terjadi di (organ limfoid) sentral maupun perifer(organ limfoid) sentral maupun perifer

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(organ limfoid) sentral maupun perifer.(organ limfoid) sentral maupun perifer.

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Central & Central & peripheralperipheralperipheral peripheral

tolerance to tolerance to self antigensself antigens

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Mekanisme AutoimunitasMekanisme Autoimunitas ::

•• HilangnyaHilangnya selfself--tolerancetolerance dapatdapat disebabkandisebabkan karenakarenaabnormalitasabnormalitas daridari seleksi/regulasiseleksi/regulasi limfositlimfosit selfself--reactivereactive &&abnormalitasabnormalitas pdpd jalurjalur pengenalanpengenalan selfself--AgAg dlmdlm sistemsistem imunimunabnormalitasabnormalitas pdpd jalurjalur pengenalanpengenalan selfself--AgAg dlmdlm sistemsistem imunimun..

•• FaktorFaktor22 ygyg berperanberperan pdpd perkembanganperkembangan autoimunitasautoimunitas ::abnormalitasabnormalitas APC/limfosit,APC/limfosit, genetik,genetik, gender,gender, kerusakankerusakanjaringanjaringan && infeksiinfeksi mikrobialmikrobial..

•• AutoimunitasAutoimunitas dapatdapat terjaditerjadi sistemiksistemik atauatau spesifikspesifik organ,organ,kemungkinankemungkinan krnkrn tipetipe AgAg && abnormalitasabnormalitas imunologikimunologik

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gg pp gg ggberbedaberbeda..

•• BerbagaiBerbagai mekanismemekanisme efektorefektor berperanberperan padapada kerusakankerusakanjaringanjaringan padapada penyakitpenyakit autoimunautoimun ygyg berbedaberbeda..

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Mechanisms of Mechanisms of t i itt i itautoimmunityautoimmunity

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Abnormalitas Limfosit penyebab AutoimunitasAbnormalitas Limfosit penyebab Autoimunitas

AbnormalitasAbnormalitas selsel TT &/sel&/sel BB AutoimunitasAutoimunitasFokusFokus :: AbnormalitasAbnormalitas selsel T,T, karenakarena ::–– ThTh :: regulatorregulator pdpd semuasemua responsrespons imunimun terhadapterhadap

AgAg proteinprotein–– BanyakBanyak penypeny.. AutoimunAutoimun berkaitanberkaitan dengandengan genetikgenetik

(MHC/HLA),(MHC/HLA), && fungsifungsi MHCMHC adladl sbgsbg molekulmolekulpenyajipenyaji AgAg pdpd selsel TT

KegagalanKegagalan selfself--tolerancetolerance pdpd selsel TT dptdpt

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KegagalanKegagalan selfself--tolerancetolerance pdpd selsel TT dptdptmenyebabkanmenyebabkan kerusakankerusakan jaringan,jaringan, melaluimelalui ::–– cellcell mediatedmediated immunimmun reactionsreactions–– ThTh autoantibodiautoantibodi.. (dapat(dapat krnkrn kegagalankegagalan selsel Ts)Ts)

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KegagalanKegagalan toleransitoleransi terhadapterhadap selfself--AgAg dapatdapat terjaditerjadi didisentralsentral && periferperifer..YgYg banyakbanyak dikupasdikupas adladl teoriteori ygyg mendukungmendukung kegagalankegagalantoleransitoleransi terjaditerjadi didi periferperifer karenakarena ::toleransitoleransi terjaditerjadi didi perifer,perifer, karenakarena ::

11.. GangguanGangguan pdpd anergy/delesianergy/delesi selsel TT spsifikspsifik selfAgselfAg maturmaturBbrpBbrp kondisikondisi mengaktivasimengaktivasi APCsAPCs jaringanjaringan &&menimbulkanmenimbulkan gangguangangguan selsel TT anergy,anergy, oleholeh adanyaadanya

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ekspresiekspresi costimulatorcostimulator && produksiproduksi sitokinsitokin..

AktivasiAktivasi APCAPC dptdpt krnkrn :: infeksi,infeksi, nekrosis,nekrosis, inflamasiinflamasi lokallokal..

ContohContoh penyakitpenyakit :: Encephalomyelitis,Encephalomyelitis, Thyroiditis,Thyroiditis, IDDMIDDM..

22.. AktivasiAktivasi LimfositLimfosit PoliklonalPoliklonal-- LPSLPS :: stimulatorstimulator bbrpbbrp cloneclone selsel BB (mice)(mice) (termasuk(termasuk selsel

BB selfself--reaktif)reaktif) dibentukdibentuk autoauto AbAb-- GraftGraft--vsvs--HostHost diseasedisease (animal)(animal) :: DonorDonor BMBM (al(al :: selsel T)T)

dikenalidikenali selsel BB resipienresipien sbgsbg asingasing interaksiinteraksi selsel TT--BBaktivasiaktivasi selsel BB poliklonalpoliklonal autoauto AbAb

33.. ReaksiReaksi SilangSilang daridari AgAg SelfSelf && AsingAsing(Molecular(Molecular mimicry)mimicry)

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-- MikrobaMikroba memilikimemiliki epitopepitop sama/miripsama/mirip dgdg proteinprotein selfself-- DemamDemam RematikRematik :: postpost streptococcalstreptococcal infinf antianti--

streptococcalstreptococcal AbAb bereaksibereaksi silangsilang dgdg proteinproteinmyocardialmyocardial humanhuman myocarditismyocarditis

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Faktor Genetik Pada AutoimunitasFaktor Genetik Pada Autoimunitas

PenyakitPenyakit autoimunautoimun mempunyaimempunyai FaktorFaktor genetikgenetik ygyg kuatkuat..IDDMIDDM (kln(kln betabeta pancreas)pancreas) 3535--5050%% pdpd kembarkembar monozigotmonozigot(( p )p ) pp gg&& 55--66%% pdpd kembarkembar dizigotdizigotGeneGene ygyg dipercayadipercaya berhubunganberhubungan kuatkuat dgdg autoimunitasautoimunitasadladl MHCMHC genes,genes, terutamaterutama MHCMHC IIII genesgenesBanyakBanyak penyakitpenyakit AutoimunAutoimun ygyg ditelitiditeliti memilikimemiliki predisposisipredisposisipdpd HLAHLA tertentutertentu..

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NonNon--MHCMHC genesgenes jugajuga berperanberperan padapada autoimunautoimun ::defisiensidefisiensi krnkrn genetikgenetik (C(C22,, CC44)) berkaitanberkaitan dgdg LupusLupus--likelikeautoimunautoimun diseasesdiseases ;; TCRTCR VV genesgenes jugajuga berkaitanberkaitan dgdgAutoimunitasAutoimunitas

autuimmune diseases have a strong genetic component, most autoimmune diseases are polygenic, and affected individuals inherit multiple genetic polymorphisms that

Genetic susceptibility

contribute to disease susceptibility, the genes are not specific & an individual susceptibility gene may contribute to different autoimmune diseases the product of many of these polymorphic genes influence the development of self-tolerance, and affected individuals expresss products of the genes that are defective in the expresss products of the genes that are defective in the maintenance of tolerance the strongest associations with autoimmunity among those genes are MHC genes especially clas II (DR,DQ alleles)

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Disease HLA allel Relative risk

Rheumatoid arthritis DR4 4DR3 5

Examples of HLA - linked immunologic disease

IDDM

DR3, 5DR4, 5-6

DR3 / DR4Heterozygote

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Multiple sclerosis DR2 4SLE DR2 / DR3 5SLE DR2 / DR3 5Phemphigus vulgaris DR4 14Ankylosing spondilitis B27 90-100

Other genes : e.g. Ig- H gene (deletion of VH gene), C2/ C4 / type I complement receptor gene deficiencies, defect / mutation in Fas & Fas ligand genes

Infeksi, Perubahan Anatomik dan Faktor lain Infeksi, Perubahan Anatomik dan Faktor lain pada Autoimunitaspada Autoimunitas

Infeksi dpt menimbulkan : aktivasi limfosit Infeksi dpt menimbulkan : aktivasi limfosit poliklonal; inflamasi lokalpoliklonal; inflamasi lokal ekspresi costimulator;ekspresi costimulator;poliklonal; inflamasi lokalpoliklonal; inflamasi lokal ekspresi costimulator; ekspresi costimulator; perubahan selfperubahan self--Ag menjadi neoAg menjadi neo--Ag krn reaksi silang; Ag krn reaksi silang; kerusakan jaringan.kerusakan jaringan.Perubahan anatomik jaringan (trauma/bahan kimia) Perubahan anatomik jaringan (trauma/bahan kimia) mendorong selfmendorong self-- Ag dikenali sistem imun.Ag dikenali sistem imun. terjadi terjadi respons imunrespons imunPengaruh Hormonal : SLE wanita 10x dari pada priaPengaruh Hormonal : SLE wanita 10x dari pada pria

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Pengaruh Hormonal : SLE, wanita 10x dari pada pria Pengaruh Hormonal : SLE, wanita 10x dari pada pria (sex hormones) (sex hormones)

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two principals mechanisms :

1. infections innate immune responses leukocytes recruitment into the tissues costimulators on tissue APC

the breakdown of T cell tolerance to self Agactivation of T cells that are not specific for

the infectious pathogen = bystander activation

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2.2. Infectious microbes may contain Ag that crossInfectious microbes may contain Ag that cross--react react with self Ag = with self Ag = mollecularmollecular mimicry:mimicry:

Rheumatic fever Rheumatic fever develops after develops after sterptococcalsterptococcal infections infections antistreptococcalantistreptococcal AbAb crosscross--react with myocardial proteins react with myocardial proteins AbAbdeposited in the heart deposited in the heart myocarditismyocarditisA Chlamydia & A Chlamydia & TrypanosomaTrypanosoma cruzicruzi crosscross--react with react with myocardial protein Ag myocardial protein Ag the the myocarditismyocarditis develop after the develop after the infectious microbes have been eliminatedinfectious microbes have been eliminated

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Exp study (animal models):Exp study (animal models):Molecular mimicry Molecular mimicry is involved in triggering autoimmunity is involved in triggering autoimmunity when the frequency of auto reactive lymphocytes is lowwhen the frequency of auto reactive lymphocytes is lowwhen the frequency of auto reactive lymphocytes is low when the frequency of auto reactive lymphocytes is low

the number is expanded by the microbial mimic of the number is expanded by the microbial mimic of the self Agthe self Ag

When the frequency of auto reactive lymphocytes is When the frequency of auto reactive lymphocytes is high, the role of microbes may be to induce tissue high, the role of microbes may be to induce tissue inflammation to recruit auto reactive lymphocytes intoinflammation to recruit auto reactive lymphocytes intoinflammation, to recruit auto reactive lymphocytes into inflammation, to recruit auto reactive lymphocytes into the tissue, & to provide 2the tissue, & to provide 2ndnd signals for the activation of signals for the activation of these bystander lymphocytesthese bystander lymphocytes

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Inflammation (possibly secondary to infections)Inflammation (possibly secondary to infections)↑↑ of the expression ofof the expression of costimulatorscostimulators

Anatomic alterations in tissues

↑↑ of the expression of of the expression of costimulatorscostimulators,,Structural alteration in self AgStructural alteration in self AgFormation of new determinants / Formation of new determinants / epitopsepitops

Ischemic injury / trauma Ischemic injury / trauma lead to the exposure of self lead to the exposure of self Ag that are normally concealed from the immune system Ag that are normally concealed from the immune system (e.g. post traumatic (e.g. post traumatic uveitisuveitis & & orchitisorchitis))

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Hormonal influences

E g SLE affectsE g SLE affects women 10x frequently as menwomen 10x frequently as menE.g. SLE affectsE.g. SLE affects women 10x frequently as menwomen 10x frequently as men

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PENYAKIT AUTOIMUNPENYAKIT AUTOIMUN

Dibedakan : organ spesifik & non organ spesifik Dibedakan : organ spesifik & non organ spesifik (sistemik).(sistemik).

Berdasar Mekanismenya :Berdasar Mekanismenya :Berdasar Mekanismenya :Berdasar Mekanismenya :Penyakit Autoimun melalui Ab :Penyakit Autoimun melalui Ab :

Anemi hemolitik autoimun (Ab panas/IgG & Ab Anemi hemolitik autoimun (Ab panas/IgG & Ab dingin/IgM) : destruksi SDM oleh Ab terhadap Ag di dingin/IgM) : destruksi SDM oleh Ab terhadap Ag di membran selmembran selMiastenia gravis : gangguan pd reseptor asetilkolin pd Miastenia gravis : gangguan pd reseptor asetilkolin pd

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hub neuromuskuler hub neuromuskuler Ig mencegah penerimaan Ig mencegah penerimaan impuls saraf impuls saraf kelemahan ototkelemahan ototTirotoksikosis : Auto Ab terhadap reseptor hormon Tirotoksikosis : Auto Ab terhadap reseptor hormon (TSH) (TSH) Grave & BasedowGrave & Basedow

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Penyakit Autoimun melalui komplex imun :Penyakit Autoimun melalui komplex imun :SLE : komplex imun mengendap di berbagai tempat SLE : komplex imun mengendap di berbagai tempat (glomerulus, arteri, sendi)(glomerulus, arteri, sendi)Rematoid Artritis : IgM (RF) yg spesifik terhadap IgGRematoid Artritis : IgM (RF) yg spesifik terhadap IgGRematoid Artritis : IgM (RF) yg spesifik terhadap IgG Rematoid Artritis : IgM (RF) yg spesifik terhadap IgG

komplex imun ditimbun di sinovial sendikomplex imun ditimbun di sinovial sendiPenyakit Autoimun melalui sel TPenyakit Autoimun melalui sel T

Thiroiditis Hashimoto : banyak pd wanita dws (goiter/ Thiroiditis Hashimoto : banyak pd wanita dws (goiter/ hipotiroidism) hipotiroidism) fs kelenjar rusak krn destruksi oleh fs kelenjar rusak krn destruksi oleh sel T sel T IDDM : kerusakan sel Beta pulau langerhans IDDM : kerusakan sel Beta pulau langerhans

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p gp gpancreaspancreas

Penyakit Autoimun melalui komplemenPenyakit Autoimun melalui komplemenDefisiensi komplemen tertentu Defisiensi komplemen tertentu SLESLE

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! once an autoimmune disease has developed, it tends! once an autoimmune disease has developed, it tendsto be chronic and often progressiveto be chronic and often progressive

the the etiology etiology of most autoimmune diseases remains of most autoimmune diseases remains obscure obscure

Other Other multifactorsmultifactors involve in involve in autoimnunityautoimnunity/autoimmu/autoimmudiseases :diseases :

genetic susceptibilitygenetic susceptibilityenvironmental triggers e.g. infectionenvironmental triggers e.g. infection

t i lt ti i ti i fl tit i lt ti i ti i fl ti i i h i h i i j t i j t

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anatomic alterations in tissues e.g. inflammationanatomic alterations in tissues e.g. inflammation, is, ischemic chemic injury, trauma, injury, trauma, hormonal : estrogenhormonal : estrogen

DiseaseDisease Presumed Presumed mediationmediation

Tissue involvementTissue involvement

GuillainGuillain--Barre syndromeBarre syndrome TT Nervous systemNervous systemMyasthenia gravisMyasthenia gravis HH Nervous systemNervous system

CLINICAL CATEGORIES :Organ / Tissue specific

Myasthenia gravisMyasthenia gravis HH Nervous systemNervous systemHashimoto’s thyroiditisHashimoto’s thyroiditis H, TH, T ThyroidThyroidGrave’s diseaseGrave’s disease HH ThyroidThyroidDiabetes mellitusDiabetes mellitus H, TH, T PancreasPancreasGoodpasture’s syndromeGoodpasture’s syndrome HH Lung and KidneyLung and KidneyPernicious anemiaPernicious anemia HH StomachStomach

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Autoimmune hemolytic diseaseAutoimmune hemolytic disease HH Red blood cellsRed blood cellsPemphigus / PemphigoidPemphigus / Pemphigoid HH SkinSkin

SLESLE HH Kidney,skin,CNS,CVKidney,skin,CNS,CV

Rheumatoid arthritisRheumatoid arthritis HH Joints,vascular bedJoints,vascular bed

Systemic

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DiseaseDisease AntigensAntigens

Diabetes mellitusDiabetes mellitus Islet Langerhans cell antigensIslet Langerhans cell antigensGoodpasture’s syndromeGoodpasture’s syndrome Basement membraneBasement membrane

Organ specific antigensOrgan specific antigens

Goodpasture s syndromeGoodpasture s syndrome Basement membraneBasement membraneGrave’s diseaseGrave’s disease TSH receptorTSH receptorHashimoto’s thyroiditisHashimoto’s thyroiditis ThyroglobulinThyroglobulinMyasthenia gravisMyasthenia gravis Acetylecholine receptorAcetylecholine receptorPernicious anemiaPernicious anemia Gastric parietal cellGastric parietal cellRheumatoid arthritisRheumatoid arthritis IgGIgG

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Rheumatoid arthritisRheumatoid arthritis IgGIgGPemphigus vulgarisPemphigus vulgaris DesmosomesDesmosomesPemphigoidPemphigoid Basement membraneBasement membraneAIHAAIHA ErythrocytesErythrocytesMale infertilityMale infertility SpermatozoaSpermatozoa

EXAMPLES OF DISEASES CAUSED BY CELLS / TISSUE SPECIFIC ANTIBODIES

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Infiltrates of lymphocytes and macrophages around the islet of Langerhans in the pancreas

Type I Diabetes mellitus

destruction of insulin-producing β cells (by DTH reactions, CTL-mediated lysis, local production of TNF & IL-1, auto-Ab) deficiency in insulin production Notes : auto- Ab : may participate in causing the disease may be a result of T cell-mediated injury l ti i k HLA DR3 DR4 / b th relative risk : HLA DR3 or DR4 / both Notes : HLA DQ2 & DQ8 often in linkage disequilibrium with DR3,DR4 viral infections e.g. coxackievirus B4 may precede the onset of IDDM

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Is a systemic disease affecting the small joints of the Is a systemic disease affecting the small joints of the extremities particularly of the fingers, as well as larger extremities particularly of the fingers, as well as larger

Rheumatoid arthritis :

e t e t es pa t cu a y o t e ge s, as e as a gee t e t es pa t cu a y o t e ge s, as e as a gejoint e.g. shoulder, elbow, knee, ankles joint e.g. shoulder, elbow, knee, ankles (synovial (synovial inflammation + destruction of the joint cartilage & bone)inflammation + destruction of the joint cartilage & bone)Both T cells & Both T cells & AbAb--mediated inflammation may contribute mediated inflammation may contribute to the development of to the development of synovitissynovitis ! ! (CD4+ T cells, (CD4+ T cells, activated B cells, plasma cells & macrophages are found activated B cells, plasma cells & macrophages are found in the in the synovitissynovitis))yy ))Numerous cytokines e.g.: Numerous cytokines e.g.: ILIL--1, IL1, IL--8, TNF, IFN8, TNF, IFNγγ have have been detected in the synovial fluidbeen detected in the synovial fluidRelatives risk: Relatives risk: HLAHLA--DR4DR4

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Is an autoimmune disease of the central nervous Is an autoimmune disease of the central nervous systemsystem

Multiple sclerosis :

systemsystem–– CD4+ T cells/Th1, react against self myelin AgCD4+ T cells/Th1, react against self myelin Ag–– DTH reaction DTH reaction activation of macrophages around activation of macrophages around

nerves in the brain & spinal cord nerves in the brain & spinal cord destruction of the destruction of the myelin, abnormalities in nerve conduction, neurologic myelin, abnormalities in nerve conduction, neurologic deficitsdeficits

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Is a rare disease, may present with signs & symptoms of Is a rare disease, may present with signs & symptoms of congestive heart failure,congestive heart failure, arrythmiasarrythmias / conduction/ conduction

Autoimmune myocarditis :

congestive heart failure, congestive heart failure, arrythmiasarrythmias / conduction / conduction abnormalitiesabnormalitiesIs generally seen as part of a systemic autoimmune Is generally seen as part of a systemic autoimmune syndrome:syndrome:–– Most commonly associate with Most commonly associate with polymyositispolymyositis –– dermatomyositisdermatomyositis, ,

SLESLE–– Less commonly with RA, scleroderma, mixed connective tissue Less commonly with RA, scleroderma, mixed connective tissue y , ,y , ,

disease, disease, sarcoidosissarcoidosis

Notes: Notes: occurrence of the occurrence of the antiribonucleoproteinantiribonucleoprotein (anti(anti--RNP) in SLE patients who develop autoimmune RNP) in SLE patients who develop autoimmune myocarditismyocarditis

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Immune complex –mediated diseases

Systemic lupus erythematosus (SLE) :

Is a chronic, remitting & relapsing, multisystem autoimmune disease

Numerous auto Ab are produced e g antinuclear antibodies (ANA) : anti doubleNumerous auto-Ab are produced e.g. antinuclear antibodies (ANA) : anti-double-stranded / native DNA ( anti-ds / anti n-DNA), Ab against ribonucleoproteins, histones, nuclear Ag, anti-Smith Ag

The principal clinical manifestations are rashes, arthritis, glomerulonephritis, vasculitis

Other manifestations e.g. hemolytic anemia, thrombocytopenia & central nerve system involvementy

RR : individuals with HLA-DR2 / DR3 (2-3x), HLA DR2 + DR3 (5x)

± 10 % deficiencies of classical pathway complement proteins especially C1q, C2/ C4

It is thought that self-Ag are released from apoptotic cells so that exposure to ultraviolet light exacerbates disease

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is associated with various infections, e.g. : is associated with various infections, e.g. :

Polyarteritis nodosa :

, g, gtubercuolosistubercuolosis, , otitisotitis media, streptococcal media, streptococcal infections & especially virus hepatitis Binfections & especially virus hepatitis B

in chronic persistent hepatitis B virus in chronic persistent hepatitis B virus circulating immune complexes (circulating immune complexes (HBsAgHBsAg><><IgMIgMspecific + complement components) specific + complement components) p p p )p p p )deposited in blood vessels deposited in blood vessels systemic systemic vasculitisvasculitis

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gangguangangguan pd pd reseptorreseptor asetilkolinasetilkolin pd hub pd hub neuromuskulerneuromuskulerIgIg mencegahmencegah penerimaanpenerimaan impulsimpuls sarafsaraf kelemahankelemahan

otototot

Myastenia gravis:

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Hyperthyroidism : Auto Ab terhadap reseptor hormon (TSH)

Graves disease (tirotoxicosis)

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DIAGNOSISDIAGNOSIS

Elevated serum gammaElevated serum gamma--globulinglobulin

Presence of diverse autoantibodiesPresence of diverse autoantibodies

Depressed level of serum complementDepressed level of serum complement

Immune complex in serumImmune complex in serum

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Depressed level of suppressor factorsDepressed level of suppressor factors

BiopsyBiopsy

1.1. Metabolic control : might be useful in certain organ specific Metabolic control : might be useful in certain organ specific disease : disease :

antithyroid drugs , vit B12antithyroid drugs , vit B12

TREATMENTSTREATMENTS

2.2. Antiinflammatory ( steroidal / nonsteroidal )Antiinflammatory ( steroidal / nonsteroidal )

Immunosuppressive cytotoxic drugImmunosuppressive cytotoxic drug

3.3. Anticholinesterase drugs / thymectomy:Anticholinesterase drugs / thymectomy:

Myasthenia gravisMyasthenia gravis

4.4. Plasmapharesis:Plasmapharesis:

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SLE, GBSyndrome, Goodpature’s syndromeSLE, GBSyndrome, Goodpature’s syndrome

5.5. Splenectomy:Splenectomy:

ITP , AIHAITP , AIHA

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