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

2. 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).

3. 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)

4. T cell development

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

6. 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).

7. 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)

8. 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

9. 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

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

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

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

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

14. Superantigens Superantigens Macrophage MHC II CDR-TCR T cell

15. EBV infection: EBNA + B cells

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

17. 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

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

19. 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

20. Mechanisms by which helminths could impact on autoimmunity and allergy

21. 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

22. 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

23. 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

24. 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

25. 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.