autoimun dr. lilia

8/8/2019 Autoimun dr. Lilia

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Autoimmune diseasesAutoimmune diseases

Interaction among macrophage, bacteria and T cell


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: Reaksi sistem imun terhadap Ag jaringan

sendiri.Kehilangan toleransi diri (self tolerance)

menyebabkan sel-sel sistem imun mengenal Agtubuh sendiri sebagai asing.


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Non-self Ags

Self Ags

Central

Tolerance

Periphe

ralTolerance

Process of Self toleranceLymph


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Positive and

negative selection

of T cells in the

thymus during the

SELF-TOLERANCEprocess

Positive and

negative selection

of T cells in the

thymus during the

SELF-TOLERANCEprocess


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AUTOIMMUNE DISEASE

Immune response to self antigens

Can be mediated by humoral ( type II and III

hypersensitivity reactions ) and / or cellular factors

( type IV hypersensitivity reaction )

Characterized by chronicity and usually

nonreversible

AUTOIMMUNE DISEASE

Immune response to self antigens

Can be mediated by humoral ( type II and III

hypersensitivity reactions ) and / or cellular factors

( type IV hypersensitivity reaction )

Characterized by chronicity and usually

nonreversible


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1. Excessive self reactive Th-cell activity

a. Altered form of self antigen (virus / drug)

b. Molecular mimicry (virus / bacteria)2. A bypass of the requisite self-reactive Th-cell

activity

a. Polyclonal activation of B cells

( LPS , Epstein-Barr virus )

3. Release of sequestered Antigens

( sperm , eye lens )

1. Excessive self reactive Th-cell activity

a. Altered form of self antigen (virus / drug)

b. Molecular mimicry (virus / bacteria)

2. A bypass of the requisite self-reactive Th-cell

activity

a. Polyclonal activation of B cells

( LPS , Epstein-Barr virus )

3. Release of sequestered Antigens

( sperm , eye lens )

ETIOLOGY

Defect of SELF TOLERANCE mechanisms


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Altered form of self-antigensAltered form of self-antigens

Drugs Diseases

-methyldopa Anemia

Penicillinamine Myasthenia gravis

Quinidine Granulocytopenia

Molecular mimicry

Shigella flexneri HLA B27

Proteus mirabillis HLA DR4

Coxsackie B virus Myocardium

Trypanosoma cruzi Myocardium

HBV Myelin basic p.


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Polyclonal activationPolyclonal activation

Activation of clones to

self antigens

Activation of clones to

self antigens


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Predisposing factors

1. Genetic factor : HLA genes

2. Sex : female > male

3. Age : frequency increased with age3. Age : frequency increased with age

Predisposing factors

1. Genetic factor : HLA genes

2. Sex : female > male

3. Age : frequency increased with age3. Age : frequency increased with age

Rheumatoid arthritisRheumatoid arthritis DR4DR4 RR. 6.0RR. 6.0

IDDMIDDM DR3/4DR3/4 RR. 2.0-5.0RR. 2.0-5.0

Hashimotos thyroiditisHashimotos thyroiditis DR5DR5 RR. 3.0RR. 3.0

Myasthenia gravisMyasthenia gravis DR3DR3 RR. 3.0RR. 3.0

Rheumatoid arthitisRheumatoid arthitis F : M 3:1F : M 3:1

SLESLE F : M 4:1F : M 4:1

Sjorgens syndromeSjorgens syndrome F : M 9:1F : M 9:1


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CLINICAL CATEGORIES :

Organ / Tissue specific

CLINICAL CATEGORIES :

Organ / Tissue specific

Disease Presumed

mediation

Tissue involvement

Guillain-Barre syndromeGuillain-Barre syndrome TT Nervous systemNervous system

Myasthenia gravisMyasthenia gravis HH Nervous systemNervous system

Hashimotos thyroiditisHashimotos thyroiditis H, TH, T ThyroidThyroid

Graves diseaseGraves disease HH ThyroidThyroid

Diabetes mellitusDiabetes mellitus H, TH, T PancreasPancreas

Goodpastures syndromeGoodpastures syndrome HH Lung and KidneyLung and Kidney

Pernicious anemiaPernicious anemia HH StomachStomach

Autoimmune hemolytic diseaseAutoimmune hemolytic disease HH Red blood cellsRed blood cells

Pemphigus / PemphigoidPemphigus / Pemphigoid HH SkinSkin

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

Rheumatoid arthritisRheumatoid arthritis HH Joints,vascular bedJoints,vascular bed

SystemicSystemic


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DiseaseDisease AntigensAntigens

Diabetes mellitusDiabetes mellitus Islet cell antigensIslet cell antigens

Goodpastures syndromeGoodpastures syndrome Basement membraneBasement membrane

Graves diseaseGraves disease TSH receptorTSH receptor

Hashimotos thyroiditisHashimotos thyroiditis ThyroglobulinThyroglobulin

Myasthenia gravisMyasthenia gravis Acetylecholine receptorAcetylecholine receptor

Pernicious anemiaPernicious anemia Gastric parietal cellGastric parietal cell

Rheumatoid arthritisRheumatoid arthritis IgGIgG

Pemphigus vulgarisPemphigus vulgaris DesmosomesDesmosomes

PemphigoidPemphigoid Basement membraneBasement membrane

AIHAAIHA ErythrocytesErythrocytes

Male infertilityMale infertility SpermatozoaSpermatozoa

DiseaseDisease AntigensAntigens

Diabetes mellitusDiabetes mellitus Islet cell antigensIslet cell antigens

Goodpastures syndromeGoodpastures syndrome Basement membraneBasement membrane

Graves diseaseGraves disease TSH receptorTSH receptor

Hashimotos thyroiditisHashimotos thyroiditis ThyroglobulinThyroglobulin

Myasthenia gravisMyasthenia gravis Acetylecholine receptorAcetylecholine receptor

Pernicious anemiaPernicious anemia Gastric parietal cellGastric parietal cell

Rheumatoid arthritisRheumatoid arthritis IgGIgG

Pemphigus vulgarisPemphigus vulgaris DesmosomesDesmosomes

PemphigoidPemphigoid Basement membraneBasement membrane

AIHAAIHA ErythrocytesErythrocytes

Male infertilityMale infertility SpermatozoaSpermatozoa

Organ specific antigensOrgan specific antigens


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DIAGNOSISDIAGNOSIS

Elevated serum gamma-globulinElevated serum gamma-globulin

Presence of diverse autoantibodiesPresence of diverse autoantibodies

Depressed level of serum complementDepressed level of serum complement

Immune complex in serumImmune complex in serum

Depressed level of suppressor factorsDepressed level of suppressor factors

BiopsyBiopsy

DIAGNOSISDIAGNOSIS

Elevated serum gamma-globulinElevated serum gamma-globulin

Presence of diverse autoantibodiesPresence of diverse autoantibodies

Depressed level of serum complementDepressed level of serum complement

Immune complex in serumImmune complex in serum

Depressed level of suppressor factorsDepressed level of suppressor factors

BiopsyBiopsy


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MACAM2 PENY. AUTOIMUN

I. Penyakit autoimun organ.

1. Autoimune hemolytic anemia (AHA)

: ok destruksi oleh AB terhadap Ag pada permukaan erythrosit

(autoantibodi antierytrosit)

2. Tyroiditis Hashimoto.

- Sebagian besar eutiroid, ttp dapat juga hipotiroid / hipertiroid.

- Dijumpai :

Autoantibodi anti tiroglobulin. Infiltrasi limfosit, makrofag, sel plasma dalam kelenjar

membentuk folikel limfoid


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3. Penyakit Grave

: Toxic goiter /exopthalmic goiter

- dijumpai Antibodi (Long acting Thyroid stimulator : LATS /

TSAb = Thyroid Stimulating AB) terhadap reseptor (TSH)

pada permukaan tiroidmerangsang kelenjar tiroid. = T3 dan

T4 >>>.


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Graves disease (thyrotoxicosis, hyperthyroidism)

An increased number of peripheral B cells correlates with severity

The number of T cells decreases particularly the CD8 cells (Ts)

Several autoantibody (IgG or IgM) against thyrotropin receptor

with different effects are produced:

1. One type of antibody blocks the binding of TSH to thyroid epithelialcells

2. A second antibody causes the proliferation of of thyroid cells

3. A third type called thyroid - stimulating antibody reactys with TSH

receptor and mimics the thyrotropin hormone

The autoantibody could cross the placenta and causes the hyperthy-

roidism in newborn

Increased frequency in HLA-B35 and DR3

Graves disease (thyrotoxicosis, hyperthyroidism)

An increased number of peripheral B cells correlates with severity

The number of T cells decreases particularly the CD8 cells (Ts)

Several autoantibody (IgG or IgM) against thyrotropin receptor

with different effects are produced:

1. One type of antibody blocks the binding of TSH to thyroid epithelialcells

2. A second antibody causes the proliferation of of thyroid cells

3. A third type called thyroid - stimulating antibody reactys with TSH

receptor and mimics the thyrotropin hormone

The autoantibody could cross the placenta and causes the hyperthy-

roidism in newborn

Increased frequency in HLA-B35 and DR3


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4. SINDROM SJOGREN.

- ditandai : keratokonjungtivitis sikka (mata kering ) ,xerostomia

(mulut kering)

- 40 % : bentuk primer

60 % berhubungan : RA, SLE, skleroderma, (darah = RF,

ANA).

- PA : infiltrasi sel B, sel T periductal lacrimal + hiperplasi ep +

obstruksi lumenatrofi asiner, fibrosis dan perlemakan


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5. Polimiositis / dermatomiositis

- Poliomisitis : peradangan otot skelet diperantarai kel. Imunologik.

- Klinik : kelemahan otot bil. Simetrik (kas : prox > dulu)

- Ok kerusakan serabut otot oleh sel T sitotoxic yang memasuki danmengitari serabut otot.

II. Penyakit Autoimun Sistemik

1. SLE (Sistemik Lupus Eritematosus)

- Penyakit demam sistemik, kronik, berulang, dengan gejalaberhubungan dengan semua jar (tu sendi, kulit, membran serosa)

- Perjalanan klinis bervariasi

Kadang gejala minimalsembuh tanpa pengobatan.

Sebagian besar : kambuh berulang remisi : dapatdipertahankan dengan imunosupresan.

Ketahanan hidup 10 tahun = + 70 %

G b kli i b i i


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- Gambaran klinis bervariasi .


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Ciri kas (tu) :

ANA (antinuclear antibodies)Sel LE (badan LE (nukleus sel yang rusak

bereaksi dengan AB antinukleus

kehilangan pola kromatin) yang difagositneutrofil / makrofag)

2. Rheumatoid arthritis (RA)

Poliarthritis (nyeri pada berbagai sendi)

Uji serologik : reumatoid faktor

(autoantibodi anti Ig G) timbul pada

persendian.


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Rheumatoid arthritis

Immunologic findings :

1. Rheumatoid factor :

anti-IgG immunoglobulin (IgM , IgG or IgA) produced by B cells in

the synovial membrane.

Has the specifity to Fc fragment of IgG

2. Immune complexes:

Complement activation which leads to inflammatory respons

Large complexes will be phagocytized by macrophage which

release cytokines and also neutrophils which release digestive

enzymes. Small complexes may circulate causing vasculitis and

lung injury

3. Antinuclear antibody could also present in patients with RA

4. Genetic background : HLA-DR4 : susceptible

HLA-DR1: protective

5. Cytokines : TNF, IFNg , IL-1 and IL-8 may participate in tissue

damage by inducing inflammatory respons and destruction.

Rheumatoid arthritis


1. Rheumatoid factor :

anti-IgG immunoglobulin (IgM , IgG or IgA) produced by B cells in

the synovial membrane.

Has the specifity to Fc fragment of IgG

2. Immune complexes:

Complement activation which leads to inflammatory respons

Large complexes will be phagocytized by macrophage which

release cytokines and also neutrophils which release digestive

enzymes. Small complexes may circulate causing vasculitis and

lung injury

3. Antinuclear antibody could also present in patients with RA

4. Genetic background : HLA-DR4 : susceptible

HLA-DR1: protective

5. Cytokines : TNF, IFNg , IL-1 and IL-8 may participate in tissue

damage by inducing inflammatory respons and destruction.


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Systemic lupus erythematosus


1. LE cell phenomena

Neutrophils with ingested nuclear material of lymphocytes

2. Antinuclear antibody : IgG or IgM to DNA

Anti ssDNA

Anti dsDNA : a complement fixing antibody

closely related to active SLE and glomerulonephritis

Anti both ss and dsDNA

3. Other antibodies :

antibodies against RNA, mitochondria, rbc, ribosome etc.

4. Genetic aspects :

HLA DR2 : more likely to produce dsDNA

5. Altered complement levels, hypergammaglobulin and low number of T

cells

Systemic lupus erythematosus


1. LE cell phenomena

Neutrophils with ingested nuclear material of lymphocytes

2. Antinuclear antibody : IgG or IgM to DNA

Anti ssDNAAnti dsDNA : a complement fixing antibody

closely related to active SLE and glomerulonephritis

Anti both ss and dsDNA

3. Other antibodies :

antibodies against RNA, mitochondria, rbc, ribosome etc.

4. Genetic aspects :

HLA DR2 : more likely to produce dsDNA

5. Altered complement levels, hypergammaglobulin and low number of T

cells


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IDDM


Destruction process mediated by:

CTL or delayed type hypersensitivity (CD4+Th1)

Antibodies against islet cells (IgG2 & IgG4) and also anti- insulin

antibodies

Genetic background :

Risk is increased in people with HLA-DR3 and DR4 haplotypes

HLA DQ variations in beta-chain alleles may confer either protection or

susceptibility.

The onset of IDDM is often preceded by viral infection : mumps, CMV,

influenza, rubella, coxsackievirus . Molecular mimicry and cross-

reactive antigens may trigger the production of the auto-antibodies

IDDM


Destruction process mediated by:

CTL or delayed type hypersensitivity (CD4+Th1)

Antibodies against islet cells (IgG2 & IgG4) and also anti- insulin

antibodies

Genetic background :

Risk is increased in people with HLA-DR3 and DR4 haplotypes

HLA DQ variations in beta-chain alleles may confer either protection or

susceptibility.

The onset of IDDM is often preceded by viral infection : mumps, CMV,

influenza, rubella, coxsackievirus . Molecular mimicry and cross-

reactive antigens may trigger the production of the auto-antibodies


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Myasthenia gravis


Antibody (IgG3) against acetylcholine receptor at the myoneural junction

causing endocytosis of the receptor

Complement could be activated causing further problems

60-80 % have enlarged thymus


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Hashimoto thyroiditis ( Chronic thyroiditis )

Immunologic findings

Various antibody to Thyroid specific antigens can be detected :

1. Antibody to thyroglobulin

2. Antibody to thyroid microsomal antigens

T cell mediayed immunity ( delayed type hypersensitivity ) could also be

demonstrated

Histologic examination shows lymphocytes and plasma cell infiltration,

disappearance of colloid and fibrosis


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TREATMENTSTREATMENTS

1.1. Metabolic control : might be useful in certain organMetabolic control : might be useful in certain organ

specific disease :specific disease :

antithyroid drugs , vit B12antithyroid drugs , vit B12

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:

SLE, GBSyndrome, Goodpatures syndromeSLE, GBSyndrome, Goodpatures syndrome

5.5. Splenectomy:Splenectomy:

ITP , AIHAITP , AIHA

TREATMENTSTREATMENTS

1.1. Metabolic control : might be useful in certain organMetabolic control : might be useful in certain organ

specific disease :specific disease :

antithyroid drugs , vit B12antithyroid drugs , vit B12

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:

SLE, GBSyndrome, Goodpatures syndromeSLE, GBSyndrome, Goodpatures syndrome

5.5. Splenectomy:Splenectomy:

ITP , AIHAITP , AIHA


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Activation

Proliferation

Differentiation

Maturation

AntibodyCell-med Hypers. PlasmapharesisImmuno-suppress

Inflammatory

Tissue damage

Metabolic defect Structural defect

Thymus graft

Thymus factor

Total ll.nn irradiation

Antigen induced

suppression

Anti inflammatory drugs

Metabolic control Tissue graft

Gene therapy

Antigen induced

tolerance

Bone marrow graft

Anti Class II

Anti CD4

Anti mitotic drugs

Anti-IL2R

Stem cell

B / T

Blast

Effector

T


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Metabolic control

Insulin : Juvenile diabetesB12 : Pernicious anemia

Anti thyroid : Grave disease

Anti-cholinesterase : Myasthenia gravis

Thymectomi : myasthenia gravis

Anti-inflammatory

Steroid : SLE

Anti-prostaglandin : Rheumatoid arthritis

Anti-TNF : Rheumatoid arthritis


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Immunosuppressive drugs

Cyclosporine A ( blocks IL-2, anti-mitotic) : uveitis , IDDM , psoriasis , ITP , Crohns

disease ,

Myasthenia gravis

Azathioprine , cyclophosphamide , methotrexate in combination with steroid : SLE , RA ,

CAH

Immunological control strategies

Cellular manipulation : anti-Class MHC Class II, anti-IL2R : SLE

Idiotype control : IV injection of Ig pool from many donors : reccurent abortion associated

with ACA

auto antibody to FVII


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Antigen manipulation

Peptide analog that will bind MHC molecule and block the response to auto-

antigen

To induce TGF production of gut mucosal system to suppress inflammatorycytokines:

multiple sclerosis patients fed with MBP

Plasmapharesis

SLE (not successful)

Goodpasteurs syndrome(successful)

autoimun dr. lilia

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