Autoimmune diseases

1. Autoimmune diseases

2. How self tolerance fails? • Imbalance between lymphocyte (T or B cells) activation and control mechanism • Defect in deletion • Low number of Treg • Defective apoptosis of self reactive lymphocytes • Inadequate inhibitory receptors • Activation of APC overcoming regulatory mechanisms

3. AUTOIMMUNE DISEASES - Organ specific: autoantibody or T cell responses against self antigens with restricted tissue distribution lead to organ-specific diseases(myasthenia gravis, type I diabetes, multiple sclerosis) - Systemic : circulating immune complexes, antibodies (SLE, RA) T and B cells participate Causes: -genetical factors -epigenetical factors -hormonal effects -environmental factors: microbes, stress , psychosomatic factors -disturbed regulation Characteristics: -multifactorial -slow appearance -remissions – regulation sometimes work -can be transferred by serum or cells AUTOIMMUNE DISEASES

4. Structuresrecognizedby T cells: • Tyroglobulin, • insulin, • acetilcholin receptor • myelin basic protein • HSP65 20 - 50% of BCR and TCR are autoreative Regulatory mechanisms provide protection of self structures Structuresrcognizedby B cells: • HSP65, HSP70, HSP90 • Enzimes: glicerinaldehid 3-phosphate dehydrogenase • Cell membrane proteins, • Intracellular proteins • DNS, histones, • Plasma proteins • Hormones • cytokines Incidence of autoimmune diseases: 3 - 8 % of the adult population Presentinhealthypersons !

5. Various effector mechanisms are responsible for tissue injury in different autoimmune diseases • immune complexes, • circulating autoantibodies, and • autoreactive T lymphocytes • The clinical and pathologic features of the disease are usually determined by the nature of the dominant autoimmune response. • Autoimmune diseases tend to be chronic, progressive, and self-perpetuating • The reasons for these features are that the self antigens that trigger these reactions are persistent, and once an immune response starts, many amplification mechanisms are activated that perpetuate the response • In addition, a response initiated against one self antigen that injures tissues may result in the release and alterations of other tissue antigens, activation of lymphocytes specific for these other antigens, and exacerbation of the disease. This phenomenon is called epitope spreading, and it may explain why once an autoimmune disease has developed, it may become prolonged and self-perpetuating.

6. Mechanisms for the induction and amplification of lupus autoimmunity Hyper-responsive B cell Pathogenic autoantibodies Lupus-prone T cells

7. Mechanism of epitope spreading

8. Mechanisms of chronicity of autoimmune diseases. Once an autoimmune reaction develops, amplification mechanisms (such as cytokines, shown as an illustrative example) promote activation of autoreactive lymphocytes, and release of self antigens from damaged cells and tissues leads to epitope spreading.

10. Disease susceptibility genes

11. 1The odds ratio approximates values of increased risk of the disease associated with inheritance of particular HLA alleles. The data are from European-derived populations.2Anti-CCP Ab, antibodies directed against cyclic citrullinated peptides. Data are from patients who test positive for these antibodies in the serum.3SE refers to shared epitope, so called because the susceptibility alleles map to one region of the DRB1 protein (positions 70-74).(Courtesy Dr. Michelle Fernando, Imperial College, London.)

12. Role of infections in the development of autoimmunity

13. Thereareseveralwaysinwhichinfectiousagentscouldbreakself-toleranceThereareseveralwaysinwhichinfectiousagentscouldbreakself-tolerance Because some antigens are sequestered from the circulation, either behind a tissue barrier or within the cell, an infection that breaks cell and tissue barriers might expose hidden antigens (first panel). A second possibility is that infectious agents might trigger expression of co-stimulators on antigen-presenting cells that have taken up tissue antigens, thereby inducing an autoimmune response (second panel). In some cases, infectious agents might bind to self proteins. Because the infectious agent induces a helper T-cell response, any B cell that recognizes the self protein will also receive help (third panel). Such responses should be self-limiting once the infectious agent is eliminated, because at this point the T-cell help will no longer be provided. Molecular mimicry might result in infectious agents inducing either T- or B-cell responses that can cross-react with self antigens (fourth panel). Polyclonal T-cell activation by a bacterial superantigen could overcome clonal anergy, allowing an autoimmune process to begin (last panel).

14. Expression of a particular HLA gene is not by itself the cause of any autoimmune disease, but it may be one of several factors that contribute to autoimmunity.

15. Amino acid changes in the sequence of an MHC class II protein correlate with susceptibility to and protection from type I diabetes Asp 57, shown in red on the backbone structure of the DQβ chain, forms a salt bridge (shown in green in the center panel) to an arginine residue (shown in pink) in the adjacent α chain (gray). The change to an uncharged residue (for example, alanine, shown in yellow in the bottom panel) disrupts this salt bridge, altering the stability of the DQ molecule Asp – Val, Ser, Ala - IDDM HLA-DQb1

16. Associations of HLA serotype and sex withsusceptibilitytoautoimmunedisease. SLE

17. Genesencodingthreefunctionalclasses of proteinsareimplicatedintheetiologyof SLE

18. Selected non-HLA genes associated with autoimmune diseases

20. Autoimmune diseases classified by the mechanism of tissue damage

21. Antibodymediateddiseases

22. Mechanisms of antibodymediateddiseases

23. Antibody-driven pathogenic mechanisms of human B cell autoimmunity

24. Recently defined TLR ligands and signalling pathways. VariousTLRsmaypromote DC maturation, survival, cytokine, chemokinesecretion. Thesemay lead tothebreak of tolerance and development of autoimmunedisease. PAMP: pathogen associated molecular pattern

25. Receptor-mediated delivery of autoantigens to Toll-like receptor 7 or Toll-like receptor 9.

26. Survival signals during B-cell maturation BAFF: B cellactivatingfactor of the tumor necrosisfactorfamily BAFF transgenicmice: T2 B cellnumberup>> MZB compartmentup

27. Modelfortheinvolvement of BAFF inperipheralimmunetolerance autoantigen

28. B cell receptors, their role in growth and activation: potential therapies for autoimmune disease. Autoimmunephenotype

29. PADs catalyze, Ca2+-dependent, imine to ketone reactions on specific peptidyl arginine side groups AutoantigensrecognizedinRheumatoidarthritis AntigenSensitivity (%) Specificity (%) Rheumatoid factor 70–75 (also present in otherdiseasecondition) Anti-perinuclear factor/ antifilaggrin/anti-cyclic citrullinated peptide 50–91 > 97 Sa(citrullinatedvimentin)≤ 40 85–95 Heavy chain binding protein (BiP)/p68 ≤ 68 > 97* Glucose-6-phosphate isomerase≤ 64 > 95* *Requires confirmation by further studies.

30. Structural changes induced by citrullination. Positive charge on arginineinteracts with negative charge on acidic induced by residues. Loss of positive charge citrullinationbreaks secondary and tertiary protein structures via intermediate form generatedby partial modification. Susceptibility for RA : presence of sharedepitop, in HLA DR betachain 3. hypervariability region  autoantibody production by B cells

31. Development of ACPA-positivity - modell L. Klareskog et al. / Seminars in Immunology 23 (2011) 92–98

32. Schematic representation of a local autoantibody-induced inflammatory network in an arthritic joint.

33. T cell mediated diseases

34. Sclerosis multiplex (SM) is a chronicinflammatoryautoimmunedisease, potentiallyleadingtodisability. Itaffects CNS (brain, spinalcord) Viralinfection(?) inflammation targetingmyelinsheet of nerves, damage of myelinsheets  damageofnerves and gliacells. Resultsin sclerosis atmultiplesites. The accutinflammationinducedamagesinconduction, leadingtoactivephase, thenrelapse. Atlaterphasenervesaredamagedtoo, and thedisease is worthened. Primaryprogressiveform is alsoexist.

35. Hashimoto thyroiditis és Graves’ betegség: Thyroid gland is affected 3 mechanisms: • Antibody mediated, • T ell mediated, • Fas mediated TH1 andTH2 cytokines play role

36. Nature Reviews Immunology2, 195 -204 (2002); doi:10.1038/nri750Giorgio Stassi & Ruggero De Maria AUTOIMMUNE THYROID DISEASE: NEW MODELS OF CELL DEATH IN AUTOIMMUNITY

37. Threedifferentmechanisms of thyrocytedepletioninHashimoto'sthyroiditishavebeensequentiallyproposed.

38. Infiltrating T cells might be killed by thyrocytes during Hashimoto's thyroiditis CD95 (Fas) jelre nagyon érzékenyek.

39. Crohn’sdisease: • Inflammatoryboweldisease (IBD) is a chronicrelapsingidiopathicinflammation of thegastrointestinaltract. The two main forms of IBD — Crohn'sdisease and ulcerativecolitis. • prevalencerange of 10–200 cases per 100,000 individualsinNorthAmerica and Europe • theincidence of Crohn'sdisease has increasedduringthepastfourdecades • Disregulatedimmuneresponsetonormalgutflora • Mutationin NOD2 (nucleotidbindingoligomerizationdomain) wasobservedCrohn: geneticallydeterminederror of innateimunity? • IL-12, IFNγ play role

40. Anatomy of mucosalinflammation and points of therapeuticattack Epidemiology Both Crohn's disease and ulcerative colitis have a prevalence range of 10–200 cases per 100,000 individuals in North America and Europe. Inflammatory bowel disease (IBD) is a chronic relapsing idiopathic inflammation of the gastrointestinal tract. The two main forms of IBD — Crohn's disease and ulcerative colitis — have many similarities, but there are also several clinical and pathological differences. In a small minority of cases that involve only the colon, they are indistinguishable and categorized as 'indeterminate colitis'.

41. Therapy: Immunosuppressiveagents – notantigenspecific steroidornon-steroidanti-inflammatoryagents Autoantigen-specifictherapy (?) but: epitopespreading Antibodytherapies : anti-CD4, etc anti-TNFa anti-CD20 Inducingtolerance: oralapplication of crossreactingpeptidemixture tolerogenicdendriticcells MHC therapy: inhibitspresentation MHC-peptidtherapy TCR-pepidetherapy