AUTOIMMUNITY, AUTOIMMUNE DISEASES Prof dr Gergely Péter Semmelweis University Central Laboratory of Immunology

The etiology of autoimmune diseases is unknown. They are diseases of variable clinical picture and prognosis, their common feature: autoreactivity (autoreactive T cells, autoantibodies) plays an important role in the pathogenesis. Features: Variable clinical picture and prognosis, even within one disease (spontaneous remissions) In the majority: Female predominance (e.g., in SLE 9:1) They frequently appear as „overlap” e.g. Sjögren’s syndrome, mixed connective tissue disease (MCTD).

The key element in the pathogenesis: loss of autotolerance The mechanism of autotolerance (see below): central tolerance (passive; occurs in the thymus, during early stage of ontogenesis) peripheral tolerance (mainly active processes, during entire life)

T cell development

Selection of T cells in the thymus wesk affinity TCR high affinity TCR intermediary affinity TCR Selection of T cells in the thymus

The key element is, therefore, the loss of autotolerance There are potentially autoreactive T and B cells in our body, which, under certain circumstances, may cause autoimmune disease. Autoreactive T cells are of utmost importance, e.g.: direct cytotoxic (CD4+ and CD8+) autoreactive T cells, e.g. in graft versus host disease (GVHD) autoreactive helper T cells: e.g. in systemic lupus erythematosus (SLE) Autoimmune reaction is a physologic process (autoantibodies, in particular of IgM class are usually not pathogenic but rather play a scavenger role).

Autoimmunity: Autoimmunity: (loss of autotolerance) causes: 1) intrinsic: genetic (MHC, TCR, IG, cytokine, etc) 2) extrinsic: hormonal (female predominance) drugs, UV, etc. (rare) infections bacteria (cross reactivity, super- antigens) viruses (cross reactivity, polyclonal B cell stimulation, ditrurben immune regulation)

EXTRINSIC FACTORS: Role of infections in triggering auto- immune diseses Cross-reacting antigens or molecular mimicry polyclonal T & B cell activation (eg. superantigenes) tissue injury – loss of barrier bystander activation epitope spreading

THE ROLE OF MHC IN DISEASE SUSCEPTIBILTY Disease HLA antigen Risk Ankylosing spondylitis (AS) B27 >150 Reiter’s syndrome B27 >40 Rheumatoid arthritis DR4 (B1*0401/04) 9 Juvenile RA (JIA) DR8 8 IDDM DQ8 14 Multiple sclerosis DR2, DQ6 12

Genetic background of SLE Gene Chromosome Importance Fc receptor: R2A 1q22-23 + R3A 1q22-23 +++ Cytokine: IL-10 1q31-32 ++++ TNF 6p21 + TNF 6p21 +++ CTLA-4 2q33 ++ MHC: HLA-DR2/DR3 6p21 ++++ Complement: C4 6p21 ++++ MBL 10q11.2-q21 + Apoptosis: PDCD-1 2q37 + FAS 10q24 + FASL 1q23 + Bcl-2 18q21 +++

SOME CROSS-REACTIVE ANTIGENS Microorganism Antigen Disease Str. haemolyticus heart muscle carditis nerves chorea Yersinia TSH-receptor Graves’ disease HLA-B27 reactive arthritis Klebsiella HLA-B27 SPA Adenovirus gluten celiac disease Trypanosoma cruzi heart muscle carditis nerves neuritis

MHC MIMICRY Microorganism/Autoantigen Amino acid sequemce MHC peptide a) Klebsiella nitrogenase QTDRED HLA-B27 QTDRED b) Tr. cruzi neuraminidase RAASPLLGA HLA peptide RMATPLLMQ Na/K ATP-ase RVAPPGLTQ c) E. coli QKRAA HLA-DR4/Dw4/DR9 EQKRAA EBV glycoprotein B QKRAA d) S antigen (uveitis) FLGELTSSEVATEV HLA-B27 ALNEDLSSWTAADT e) IRBP YLRFDSFA HLA-B27 FVRFDSDA

HEAT SHOCK PROTEINS (Hsp) Hsp Family (kD) Microorganism hsp 90 Pl. falciparum, Sch. mansoni hsp 70 M. tuberculosis, M. leprae Chl. trachomatis hsp 60 (GroEL) M. tuberculosis, M. leprae, B. burgdorferi GroES M. tuberculosis

Superantigens Superantigens Macrophage MHC II CDR-TCR T cell

EBV infection: EBNA + B cells

SUPERANTIGENS AND THEIR TCR Vß SPECIFICITY Bacterial exotoxins TCR Vß St. aureus enterotoxin A 1.1, 5.6, 7.3-4, 9.1 B 3, 12, 14, 15, 17, 20 C1 3, 6, 12, 15 Str. haemolyticus toxic shock protein (TSST-1) 2 erythrogenic toxin A 8, 12, 14, 15 B 2, 8 C 1, 2, 5.1 Retroviruses: HIV

THE ROLE OF RETROVIRUSES IN THE ETIOPATHOGENESIS OF AUTOIMMUNE DISEASES HTLV-I uveitis sarcoidosis Sjögren’s syndrome arthritis myositis (myopathia) pneumonitis Endogenous retroviral sequences (ERV) kryoglobulinemia scleroderma (PSS) SLE RA

RETROVIRUS Transformation RETROVIRUS tax gene expression Oncogene cell proliferation tissue destruction RETROVIRUS tax gene expression cytokine production immuno- proliferation Cell activation Inflammation

Quiescent Quiescent (suppressed) Autoimmune disease state inflammation, tissue injury potential autoreactive cells regulatory epitope disturbance spreading antigene mimicry, polyclonal mitogens activation, clonal expansion, B cell activation no help help activation, proliferation autoantibody production T cell activation regulatory disturbances, in part, due to genetic background T T B B

Mechanisms by which helminths could impact on autoimmunity and allergy

Infectious agents, or their products, that prevent autoimmunity Agent or product Autoimmune disease Schistosoma mansoni Type 1 diabetes, EAE, Graves’ Schistosoma mansoni eggs Type 1 diabetes, EAE, experimental colitis Soluble Schistosoma mansoni Type 1 diabetes egg and worm products Hymenolepis diminuta Experimental colitis Acanthocheilonema viteae Collagen-induced arthritis secreted product (ES-62) Trichuris suis Crohn’s disease Heligmosomoides polygyrus Inflammatory bowel disease Trichinella spiralis Experimental colitis Trypanosoma brucei Collagen-induced arthritis Mycobacterium bovis Type 1 diabetes, EAE Mycobacterium avium Type 1 diabetes Streptococcus sanguinis* Collagen-induced arthritis Bordetella pertussis Experimental allergic encephalomyelitis

PATHOGENIC PROCESSES IN AUTOIMMUNE DISEASES: a) autoantibodies: direct cytotoxicity - complement/lysis - enhanced phagocytosis inhibition of function - myasthenia stimulation - TSI cell activation - ANCA antiphospholipid antibodies - thrombosis other - intracellular antigens (ANA) b) IC disease – key feature of SLE c) T cells perforin - necrosis granzyme B - apoptosis both Th1 & Th2 cytokines

EXPERIMENTAL AUTOIMMUNE DISEASES Spontaneous: NZW mice  hemolytic anemia, lymphoma, NZWxNZB F1 mice  SLE: glomerulonephritis, ANA BXSB mice  SLE (in males) ANA, glomerulonephritis lpr gene mutant mice (Fas apoptosis gene defect lympho- proliferation: MLR/lpr  SLE; C57BL6/lpr  minimal disease ‘viable motheaten’ (mev) mice  neonatal autoimmune disease: anti-DNA, hypergammaglobulinemia (B cell maturation defect) TGF- knock-out mice  severe systemic autoimmune disease, the disease can be transferred by T cells. IL-2, and IL-4 deficient mice display signs mainly of enteral autoimmune disease (depens on enteral flora). bcl-2 oncogene transgenic mice  ANA ‘tightskin’ (tsk gene mutant) mice  scleroderma (skin, lung, heart disease); no skin disease in CD4 deficient mice. NOD mice  IDDM BB rats  IDDM

EXPERIMENTAL AUTOIMMUNE DISEASES (Cont’d) b) Induced Pristane-induced SLE in mice (also genetically determined, e.g. C57BL mice are resistant) Experimental allergic encephalomyelitis (EAE) - Lewis rats + myelin basic protein (MBP) adjuvant arthritis collagen (II), and peptidoglican-induced arthritis (HTLV-I tax) transgenic mice: RA/SS-like disease

HUMAN AUTOIMMUNE DISEASES Systemic systemic lupus erythematosus (SLE) antiphospholipid syndrome (APS) rheumatoid arthritis (RA) Sjögren’s syndrome (SS) scleroderma mixed connective tissue disease (MCTD) myositis group UCTD and overlap chronic graft versus host disease (GVHD) Organ-specific e.g. Hashimoto, AIHA, ITP, etc.