Autoimmunity , immun o toleranc e

1. Autoimmunity, immunotolerance http://xenia.sote.hu/depts/pathophysiology László Tornóci Semmelweis University Institute of Pathophysiology

2. Definition of autoimmunity The immune system mounts an attack against the tissues of its own host without a clear reason. Implicit statements: • If we know the reason of the immune reaction, it is not called autoimmunity (e.g. viral infection) • The immune system can distinguish between self and non-self (dogma) • The immune system will not attack tissues recognized as self (the concept of tolerance)

3. The frequency of autoimmune diseases • 4-5% of the population affected • Highest prevalence (cca. 1-1%): • Autoimmune diseases of the thyroid (Graves disease, Hashimoto thyreoiditis) • Rheumatoid arthritis (RA) • A few dozens of rare diseases also belong to this group

4. Graves (Basedow) dis. Hashimoto thyreoiditis Pernicious anemia Addison’s disease DM type 1 Myasthenia gravis Guillain-Barré sy. SLE RA Scleroderma Dermatomyositis Vasculitis Clinical classification of autoimmune diseases organ specific systemic

5. Significance of autoimmune diseases • Potentially fatal disease (e.g. DM type 1, pernicious anemia) • Lifelong treatement is necessary • They cause severe, progressive inflammatory reactions (the systemic ones)

6. Frequently affected organs systemic diseases organ specific diseases

7. Combined occurrance of autoantibodies systemic diseases organ specific diseases

8. Occurrence of autoantibodies in a family Presence of an autoantibody by itself doesn’t necessarily cause clinical symptoms!

9. Hashimoto thyreoiditis 1 Clinical picture enlargement of the thyroid gland

10. Hashimoto thyreoiditis 2 Histological picture of the thyroid healthy Hashimoto thyreoiditis

11. SLE: systemic lupus erythematodes A frequent and most typical symptomof the disease is a butterfly-shaped erythema on the cheeks. It is caused by photosensitivity. The tissue damage occurs by the type 3 hypersensitivity reaction. The symptoms are very variable, depending where the circulating immune complexes get deposited, causing an inflammatory reaction.

12. MHC I, II complement apoptosis CTLA-4 TNF- infection (molecular mimicry) fetal/neonatal infection haptens (drugs) Causes/risk factors inherited/genetic acquired

13. Inherited/geneticfactors Susceptibility to autoimmune disease was linked to more than two dozens of genes in mice experiments. Only a few examples are presented here.

14. The role of MHC I, II alleles • In most autoimmune diseases, certain MHC alleles were found to be risk factors • Some alleles can be protective (e.g.in DM type 1) • Some alleles are risk factors in certain races only Antigensget presented associated with MHC, so the efficiency of the presentation of a particular antigen (and the possibility of an autoimmune reaction) may be determined by MCH alleles.

15. The role of complement The first few members of the complement system (C1, C4, C2, C3) play an important role in the elimination of immune complexes. Immune complexes carrying C3b are bound to RBCs, get taken up by the RES, where they are degraded. Congenital deficiency of C1,C2,C3,C4 frequently leads to autoimmunediseases (the pathomechanism of the tissue damage is type 3 hypersensitivity reaction).

16. The role of apoptosis A mutation in the genes regulating apoptosis can cause autoimmunity

17. A: lymphadenopathy B-E: lymph node • B: HE staining • hyperplasia, • plasmocytosis C: CD3+staining D: CD4+staining E: CD8+staining ALPS: Autoimmune lymphoproliferative syndrome A rare congenitaldisease: chronic, nonmalignantproliferation of lymph nodes, splenomegaly, large number of double negative (CD3+, CD4, CD8) ly, autoimmunephenomena. Ann Intern Med (1999) 130: 591

18. Mutationin the Fas/CD95 gene Overexpression of IL-10 Autoantibodies positive Coombs test anticardiolipin, antinuclear antibodies Cytopenias of autoimmuneorigin RBC (AIHA) platelet (ITP) neutrophil ALPS Autoimmunephenomena Pathogeneticfactors

19. The signaling system of apoptosis

20. The role of CTLA-4 CTLA-4 = cytotoxic-T-lymphocyte-associated protein 4 (CD 52). A receptor protein on the surface of T cells, through which activated T cells can get deactivating signals. • An inheritedmutation of the gene, which causes • slight changes in the function of the receptor • is associated with the following diseases: • Autoimmunediseases of the thyroid • DM type 1 • Primary biliary cirrhosis

21. Acquired/environmental factors • infection (superantigens, molecular mimicry) • fetal/neonatal infections • haptens (e.g.drugs)

22. The outbreak autoimmune diseases is frequently preceded by a viral infection sounds possible Infections are very common, autoimmunity is not Molecular mimicry 1 If an antigen of a microbe is identical or very similar to an antigen of the body(molecular mimicry),then infection by the microbe can activate clones which are originally autoreactive or capable of cross-reacting with the self antigen. For: Against:

23. Molecular mimicry 2 Molecular mimicry is implicated in the pathogenesis of the following diseases (no direct proof is available yet in any of them):

24. Guillain-Barré syndrome An acute demyelinating polyneuropathy causing paralysis. The paralysis is typically “ascending” (starts at the feet, and spreads upwards). Many cases are preceded by Campylobacter jejuni infection (especially of serotype O:19). Antibodies against ganglioside (GM1) appear in the blood as a result of the infection.

25. The role of fetal/neonatal infections If the titer of maternal Ig-s is low, the cytopathogenic and immune mediated damaging effects of the infection can lead later to autoimmune disease (e.g. DM type 1). Zinkernagel This theory can explain why there is a parallel increase of DM with better hygienic standards. NEJM (2001) 345: 1331

26. Many drugs cause hemolytic anemia, thrombocytopenia, neutropenia, or SLE-likedisease with an autoimmune mechanism. The role of haptens Many autoimmunedisease shows geographical variation. The role of gliadin in the development of celiac disease is also proven.

27. Therapeuticalpossibilities Classic approach: generalinhibition of inflammation, immunosuppression New methods: Inhibition of TNF-: RA, Crohn disease Inhibition of IL-10: SLE Destroy the immune system, then transplant allogenic stem cells: severe SLE

28. The mechanism of tolerance 1 The first theory (not accepted any more): tolerance= deletion of forbidden clones, i.e. autoimmune disease= presence of autoreactiveclones Examples ofhaving autoreactive autoantibodies: • antibodies against myocardial cells after AMI • antiphospholipid antibodiesin a number of infections The transient presence of autoantibodies occurring after major tissue damage is accepted nowadays a normal part of the inflammatory reaction.

29. The mechanism of tolerance 2 Central tolerance The majority of forbidden clones get destroyed by apoptosis (T cells in the thymus, B cells in the bone marrow). There are a number of proofs that the deletion of forbidden clones is not complete. Autoreactive T and B clonesare always present in healthy individuals. So an additional, so called peripheral tolerance mechanism must exist.

30. One experimental proof of peripheral tolerance The GP mice expressed LCMV-GP on the surface of pancretic  cells. The TCR mice had T cells with TCRs recognizing GP. The TCR-GP double transgenicmice had both. All 3 mouse strains were apparently healthy.But LCMV viral infection caused the development of DM:

31. The mechanism of tolerance 3 Tolerance is achieved by at least two levels of protection

32. Hereticideas Maybe the job of the immune system is not to distinguish self from non-self. Two new models of the immune system: „Danger” model Homeostatic theory