AUTOIMMUNITY, AUTOIMMUNE AUTOIMMUNITY, AUTOIMMUNE DISEASESDISEASES

AUTOIMMUNITY, AUTOIMMUNE AUTOIMMUNITY, AUTOIMMUNE DISEASESDISEASES

Prof dr Gergely Péter

Semmelweis UniversityCentral 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

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:

(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, polyclonalB cell stimulation, ditrurben immuneregulation)

EXTRINSIC FACTORS:Role of infections in triggering auto-

immune diseses

1) Cross-reacting antigens or molecular mimicry 2) polyclonal T & B cell activation

(eg. superantigenes) 3) tissue injury – loss of barrier4) bystander activation5) epitope spreading

THE ROLE OF MHC IN DISEASE SUSCEPTIBILTY

Disease HLA antigen Risk

Ankylosing spondylitis (AS) B27 >150Reiter’s syndrome B27 >40Rheumatoid arthritis DR4 (B1*0401/04) 9Juvenile RA (JIA) DR8 8IDDM DQ8 14Multiple sclerosis DR2, DQ6 12

Genetic background of SLE

Gene Chromosome ImportanceFc 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 choreaYersinia TSH-receptor Graves’ disease HLA-B27 reactive arthritisKlebsiella HLA-B27 SPA Adenovirus gluten celiac diseaseTrypanosoma cruzi heart muscle carditis nerves neuritis

MHC MIMICRYMicroorganism/Autoantigen Amino acid sequemce MHC peptide

a) Klebsiella nitrogenase QTDRED HLA-B27 QTDREDb) Tr. cruzi neuraminidase RAASPLLGA HLA peptide RMATPLLMQ Na/K ATP-ase RVAPPGLTQc) E. coli QKRAA HLA-DR4/Dw4/DR9 EQKRAA EBV glycoprotein B QKRAAd) S antigen (uveitis) FLGELTSSEVATEV HLA-B27 ALNEDLSSWTAADTe) IRBP YLRFDSFA HLA-B27 FVRFDSDA

HEAT SHOCK PROTEINS (Hsp)

Hsp Family (kD) Microorganism

hsp 90 Pl. falciparum, Sch. mansonihsp 70 M. tuberculosis, M. leprae Chl. trachomatishsp 60 (GroEL) M. tuberculosis, M. leprae, B. burgdorferiGroES M. tuberculosis

Superantigens

Macrophage

CDR-TCR

T cell

superantigen

MHC II

EBV infection: EBNA + B cells

SUPERANTIGENS AND THEIR TCR VßSPECIFICITY

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, 15Str. haemolyticus toxicshock protein (TSST-1) 2 erythrogenic toxin A 8, 12, 14, 15 B 2, 8 C 1, 2, 5.1Retroviruses:HIV

THE ROLE OF RETROVIRUSES IN THE ETIOPATHOGENESIS OF AUTOIMMUNE

DISEASESHTLV-I uveitis sarcoidosis Sjögren’s syndrome arthritis myositis (myopathia) pneumonitisEndogenous retroviral sequences (ERV) kryoglobulinemia Sjögren’s syndrome scleroderma (PSS) SLE RA

Cell activation

tax geneexpression

cytokine production

immuno-proliferation

Transformation

Oncogeneexpression

cell proliferation

tissue destruction

InflammationInflammation

RETROVIRUS

T

B B

T

Quiescent (suppressed) Autoimmune diseasestate inflammation, tissue

injury

antigene mimicry,polyclonal mitogens

activation, clonal expansion, B cell activation

nohelp help

activation, proliferation autoantibody production T cell activation

regulatory disturbances, in part, due to genetic background

potential autoreactivecells

regulatory epitopedisturbance spreading

Mechanisms by which helminthscould 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

colitisSoluble Schistosoma mansoni Type 1 diabetesegg and worm productsHymenolepis diminuta Experimental colitisAcanthocheilonema viteae Collagen-induced arthritissecreted product (ES-62)Trichuris suis Crohn’s diseaseHeligmosomoides polygyrus Inflammatory bowel diseaseTrichinella spiralis Experimental colitisTrypanosoma brucei Collagen-induced arthritisMycobacterium bovis Type 1 diabetes, EAEMycobacterium avium Type 1 diabetesStreptococcus sanguinis* Collagen-induced arthritisBordetella pertussis Experimental allergic encephalomyelitis

PATHOGENIC PROCESSES IN AUTOIMMUNE DISEASES:

a) autoantibodies:direct cytotoxicity - complement/lysis -

enhanced phagocytosisinhibition of function - myastheniastimulation - TSIcell activation - ANCAantiphospholipid antibodies - thrombosisother - intracellular antigens (ANA)

b) IC disease – key feature of SLEc) T cells

perforin - necrosisgranzyme B - apoptosis

both Th1 & Th2 cytokines

EXPERIMENTAL AUTOIMMUNE DISEASES

a) 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 minimaldisease

• ‘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 deficientmice 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

1. Systemicsystemic lupus erythematosus (SLE)antiphospholipid syndrome (APS)rheumatoid arthritis (RA)Sjögren’s syndrome (SS)sclerodermamixed connective tissue disease (MCTD)myositis group UCTD and overlapchronic graft versus host disease (GVHD)

2. Organ-specific e.g. Hashimoto, AIHA, ITP, etc.