Imunodefisiensi

Rachmat Gunadi

Pendahuluan
Imunodefisiensi : suatu keadaan dimana sistem imun tidak berfungsi dengan benar sebagaimana mestinya sebagai sistem pertahanan tubuh manusia. Konsep : Kolonel Ogden Brutton 1952.

Aktifitas Pertahanan Tubuh :

Pertahanan permukaan tubuh (kulit, mukosa) Fagositosis & Bakterisidal Peradangan Respon Antibodi Respon Selular

Penyebab Kegagalan Imun :

Genetik Defisiensi metabolisme dan biokimia Devisiensi vitamin dan mineral Gangguan embriogenesis Penyakit autoimun Defisiensi imun didapat

Klasifikasi Imunodefisiensi :
WHO : 1. Primer 2. Sekunder

Imunodefisiensi Primer
Dibagi menjadi : Spesifik (Adaptif) Non spesifik (Innate/Alamiah/Bawaan)

Immune Responses

Immune system protect the individual from pathogens

Rina-Susilowati 20 May 2010 3

Imunodefisiensi Primer Non Spesifik

(Alamiah) Dibagi menjadi : Defisiensi sel fagositik Defisiensi sistem komplemen

Imunodefisiensi Primer Spesifik

(Adaptif) Dibagi menjadi : Defisiensi sel T Defisiensi sel B

Adaptive Immune Responses

Immune system protect the individual from pathogens

Rina-Susilowati 20 May 2010 7

Defisiensi Limfosit B (Antibodi)

Kadar antibodi turun Hipogamaglobulinemia : semua imunoglobulin Bentuk lain : spesifik tertentu imunoglobulin Ig M, Ig G, Ig A Gejala : Infeksi berulang, Alergi

Immunodeficiency: B Cell Development

Defisiensi Ig A selektif
Paling sering dijumpai 1: 800 dari populasi normal (Ammann 1971) Perdebatan normal / tidak Berhubungan dengan atopi Kongenital : genetik (kromosom x) : pria

Defisiensi Limfosit T
Jarang Biasanya disertai dengan gangguan limfosit B Sub populasi :
Limfosit T Sitotoksik Limfosit T Helper Limfosit T Supresor (Mudah mengalami infeksi)

Defisiensi Limfosit T
Sindroma DiGeorge Aplasia / Hipoplasia kelenjar timus kongenital Sering disertai gangguan pertumbuhan wajah, tyroid, jantung. Limfosit T yang diproduksi terdapat gangguan pembentukan surface antigen. Terapi : transplantasi kelenjar tymus janin

Defects in thymus structure or thymocyte homing, blocks T cell development and induces severe immunodeficiency

Deletion of the gene TBX1 that encodes the transcription factor, T-box 1.

Defects in antigen presentation induces selective Immunodeficiency of the corresponding MHC class-restricted T cells

Severe Combined Immunodeficiency Disease (SCID)

Kegagalan stem sel berdiferensiasi : sel T / B Rentan Infeksi Virus, Bakteri, Parasit, Jamur Lab : Limfopenia Bila tidak diobati meninggal dalam 1 tahun Terapi : Transplantasi sumsum tulang Tidak boleh vaksinasi : organisme hidup yang dilemahkan

Severe Combined Immunodeficiency Disease (SCID)

Genetik : autosom resesif, kromosom x Defisiensi enzim Adenosine Deaminase (ADA) Penyakit :
Ataxia teleangiektasia Wiskott Aldrich Syndome
Tanpa pengobatan bertahan 3 tahun

Bare lymphocyte syndrome

Distinct mutations in the VDJ gene recombination or DNA repair machinery cause severe combined immunodeficiency syndromes

Defects in purine degradation leads to major combined immunodeficiency syndromes due to the accumulation of nucleotide metabolites that are toxic for developing T and B cells

Defects in the purine degrading enzymes adenosine deaminase (ADA) or purine phosphorylase (PNP) totally block lymphoid cell development

Defects in T cell development or activation lead to major immunodeficiency syndromes that underline the critical regulatory role of T cells in the immune system

Gangguan fungsi Fagositik

Netrofil & Makrofag Penyebab :
Ekstrinsik Antibodi, komplemen, limfokin Intrinsik Metabolisme : def enzim G6PD, myeloperoxidase, alkalifosfatase, enzim lisosom. Fungsi abnormal mikrotubuli : Chediak Higashi Syndrome

Gangguan fungsi Fagositik

Chronic Granulomaous Disease (CGD) : Defisiensi oksidase NADPH Gangguan pembentukan hidrogen peroksida Fungsi : membunuh mikroorganisme Kronik, mulai umur 2 tahun, pada Laki-laki Genetik : kromosom x, autosom resesif Terapi : transplantasi sumsum tulang

Gangguan fungsi Fagositik

Leukocyte Adhesion Deficiency (LAD) : Autosom resesif Kekurangan komponen glikoprotein pada permukaan leukosit : sulit menempel Granulosit, monosit, limfosit Terapi : transplantasi sumsung tulang

Defects in phagocytic cells permit widespread bacterial infections

Gangguan Komplemen
Gangguan opsonisasi, kemotaktis, kompleks imun Infeksi berulang, Autoimun. Genetik : Autosom resesif Defisiensi C1, C2, C3, mirip SLE C1 : Hereditary angioneurotic edema C3 : glomerulonefritis kronik PNH (Paroxismal Norcturnal Hemoglobinuria) : defisiensi decay accelerating factor -> komplemen

Defects in complement component cause defective humoral immune function

Defects in complement component are associated with susceptibility to bacterial infections and accumulation of immune complexes

Defect in cytokine production or action can cause immunodeficiency

A defect in the c receptor causes X-linked severe combined immunodeficiency X-linked SCID

Imunodefisiensi Sekunder
Gangguan sistem imun akibat penyakit lain Sel T / B menghilang, gangguan fungsi Penyebab : obat-obatan kangker, infeksi bakteri, keganasan sumsum tulang (leukemia), HIV AIDS

Acquired immune deficiency syndrome (AIDS)

a disease without borders

HIV is a RNA retrovirus of the lentivirus family that infects mainly CD4 T cells

Macrophage-tropic HIV variant bind to CCR5 on macrophages DC, & CD4 T cells
Lymphocyte-tropic HIV variant bind only to CXCR4 on activated CD4 T cells

Imunodefisiensi : Keganasan Sel T/B

Gamopati Keganasan sel plasma Proses translokasi sepotong kromosom ke kromosom lain Contoh : Burkit lymphoma, keganasan sel B setelah infeksi virus Eibstein Barr Virus, keganasan sel T yang dapat mengalami translokasi kromosom 8 -> 14.

Diagnosis
Membutuhkan alat yang canggih Di Indonesia jarang, terutama di kota besar Ahli yang kompeten

Bone marrow transplantation or gene therapy can be useful to correct genetic defects of the immune system.
Bone marrow donor and recipient must share at least some MHC molecules to restore immune function

Shared MHC of type b (blue).

Unshared donor MHC of type a (yellow).

But an immune reaction against the graft must be avoided or controlled to prevent a graft rejection
Graft-versus-host disease:
Mature T cells from graft attack cells of the host.

Host-versus-graft response:
Competent T cells of the host can attack the donor bone marrow stem cells

T cell depletion of the donor bone marrow prevents graftversus-host disease.

Autoimunitas & Autoimmune Disease

 Autoimunitas vs penyakit autoimun Autoimunitas : autoantibodi / reaktivitas sel T Autoimunitas tidak selalu penyakit autoimun Autoimunnitas bisa :
Penyebab penyakit autoimun Akibat penyakit autoimun Tidak berhubungan tetapi ditemukan berbarengan dengan penyakit autoimun

AUTOIMMUNITY VS. AUTOIMMUNE DISEASE

Autoimmunity Existence of harmless self-reactive lymphocytes and antibodies Potentially reversible Incidence higher in older age Significance unclear, possibly physiological Autoimmune disease Dependent on genetic viral and hormonal factors Features of severe tissue damage Clinical symptoms Protracted course but usually fatal Familiar clustering

AUTOIMMUNE DISEASE KEY CONCEPTS

Recognition of autoantigens by lymphocytes is critical Tissue destruction not just autoimmune cells must be present AD involve self-reactive T cells AD induction almost always depends on triggering of autoreactive CD4+ T cells

Self Tolerance

SUCCES
FAIL

HEALTHY PERSON

AUTOIMMUNITY

AUTOIMMUNE DISEASE

Breaking self-tolerance
Damage

Environmental factors

Infection Chemical/ Drugs

Genetic factors
- HLA-type - AIRE mutations - Antigen clearance - Signaling - Costimulation - Cytokines

Immune dysregulation

Hormones

Auto immune disease

Causes of Autoimmunity
Susceptibility genes (usually multiple) Loss of tolerance ( break down of tolerance ) Triggering factors (probably environmental)

Auto reactive T cells activation

Auto reactive B cells activation

Inadequate regulatory mechanism

Pathogenesis of autoimmune diseases

Environment Hormones Stochastic factors

Autoimmunity (loss of tolerance)

Genetic factors

Critical threshold

Initiation of pathogenesis Dendritic cell

IFN? Secretion T independent Ab production Increased activity B cell
Defective priming

Autoreactive T and B cells activation

Defective Antigen presentation T cell Increased activity

Increased costimulation Cytokine help Auto Ab production

Inflammation Disease

Abnormal complement fixation Defective phagocyte activation Circulating immune complex

Increased apoptosis Defective AICD Defective cytokine production

Tissue damage

No 1 2 3 4 5

Penyakit Autoimun Rematoid artritis Hashimoto tiroiditis Multipel sklerosis Miastenia gravis SLE

Wanita : Pria 5:2 10 : 1 2:1 2:1 9:1

Patofisiologi Penyakit Autoimun

T-Sel Bypass - Sistem kekebalan tubuh yang normal memerlukan aktivasi sel B oleh sel T sebelum dapat menghasilkan antibodi dalam jumlah besar. Kebutuhan sel-T bisa di bypass seperti contoh infeksi oleh organisme yang memproduksi super antigen yang mampu memulai aktivasi poliklonal sel B

 T-Sel-B-Cell abnormal Penyimpangan Sel B yang dimediasi oleh reseptor Molekular Mimikri Idiotype Cross-Reaksi Disregulasi sitokin Dendritic apoptosis sel Epitop drift

Molecular Mimicry

Nat Rev Imm 2009

Bystander Activation

Nat Rev Imm 2009

Epitope spreading

Nat Rev Imm 2009

Function of Treg cells

Treg cells are crucial for the induction and maintenance of peripheral tolerance to self-antigens

Treg

Teff

T eff T reg
Infection Cancer

Autoimmun e diseases

Treg

Teff

Mekanisme Autoimun
Terdapat beberapa mekanisme autoimun yaitu:
Spontan Manipulasi imunologis Manipulasi genetik

Terapi
Sulit Membutuhkan kerjasama berbagai bidang ilmu kedokteran Obat masih diteliti Perkembangan ilmu sangat pesat

Ringkasan
Immunodefisiensi : dapat terjadi pada siapa saja dan pada tingkat yang berbeda-beda Penatalaksanaan masih sulit Perlu penelitian lebih lanjut