1. Autoimmune diseases

2. CENTRAL TOLERANCE IS INDUCED AND MAINTAINED IN THE BONE MARROW AND THYMUS Clonal deletion of self agressive B and T cell clones (not complete) B AND T CELLS WITH SELF REACTIVITY ARE PRESENT IN THE AVAILABLE PERIPHERAL T CELL REPERTOIRE PERIPHERAL TOLERANCE Maintenance of self tolerance of T-lymphocytes against tissue- specific self proteins which are not represented in the thymus Active mechanisms at the level of CD4+ helper T-lymphocytes AUTOIMMUNE DISEASES Disturbance of tolerance Misdirected adaptive immunity to healthy cells and tissues

3. Normal tissue cells do not express MHC class II NO SIGNAL 1. for CD4+ Th activation Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokines NO SIGNAL 2. for CD4+ Th activation Migration of naive T lymphocytes to normal tissues is limited Antigen presenting cells are not activated in normal tissues NO SIGNAL 3. PERIPHERAL TISSUES TOLERIZE THEMSELVES PERIPHERAL TOLERANCE IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY

4. FACTORS INVOLVED IN THE PATHOMECHANISM OF AUTOIMMUNE DISEASES Lack of AICD – mediated clonal deletion –Mutation in Fas or FasL Block of anergy –Induced by tissue necrosis or local inflammation  breaking T cell anergy by increased B7 expression Novel Th epitóp  self reactive B cell activation  drug induced hemolytic anemia Inefficiency of regulatory T cell function Molecular mimicry –cross reactivity of pathogenic and self proteins Polyclonal lymphocyte activation –LPS, szuper antigens Immunologically previledged sites  Demage of anatomical barriers –Post-traumic uveitis ANY CHANGE DISTURBING THE PHYSIOLOGICAL THRESHOLD

5. Chronic inflammatory conditions Repair mechanisms cannot compete with tissue destruction caused by the immune system Variety of symptoms and of target tissues Mechanisms of recognition and effector functions are the same as those acting against pathogens and environmental antigens Both genetic and environmental factors are involved in the pre- disposition to autoimmune diseases –HLA class I and II and other genetic factors affect susceptibility Runs in families and varies between populations C1, C2 or C4 deficiency predisposes to systemic lupus erythematosus (SLE) –Environmental factors Goodpasture’s syndrome – autoantibodies to type IV collagen, glomerulonephritis, smokers develop pulmonary hemorrhage as well Symphathetic ophtalmia – provoked by damage Infection – Wegener’s syndrome – antibodies to proteinase-3 of neutrophil granules results in destruction of small blood vessels primarily in the lung Any infection can induce granulocyte activation and exposure of the autoantigen AUTOIMMUNE DISEASES

6. Frquency of autoimmune diseases is elevated in vomem

7. Tolerance : Role of genetic and environmental factors Practically all autoimmune diseases Involve some T-cell defects In the absence of T cell help autoreactive B cells ate trapped in the T-cell zone and die

8. Defective central tolerance: A utoimmune PolyEndocrinopathy Candidiasis-Ectodermal Dystrophy (APECED), AIRE deficiency (Finnish population) Heterogenous disease: Candida albicans infection hypothyroidism hypogonadism and infertility vitiligo (depigmentation of the skin) alopecia (baldness) pernicious anemia chronic active autoimmune hepatitis

10. Regulatory inhibit the activation of autoreactive T-cells IPEX: Immune dysregulation, Polyendocrinopathy, enteropathy, and X-linked syndrome FoxP3 deficiency

11. DiseaseHLA serotype Relatív riskSex ratio Women/male Ankylosing spondylitisB2787.40.3 Acute anterior uveitisB2710.04<0.5 Goodpasture’s syndromeDR215.9~1 Multiple sclerosisDR24.810 Graves’s diseaseDR33.74 - 5 Myasthenia gravisDR32.5~1 Systemic lupus erythematosusDR35.810 - 20 Insulin dependent diabetes mellitus DR3 and DR4 3.2~1 Rheumatoid arthritisDR44.23 Pemphigus vulgarisDR414.4~1 Hashimoto thyroiditisDR53.24 - 5 ASSOCIATIONS OF HLA ALLOTYPE WITH SUSCEPTIBILITY TO AUTOIMMUNE DISEASE Maximum 20% of predisposed people develop the disease  environmental factors

12. TISSUE-SPECIFIC AUTOIMMUNE DISEASES Endocrine glands Tissue-specific proteins are not expressed in other cells Vascularized tissues, secrete hormone to the blood –Easy access to the immune system Impaired function of a single type of epithelial cells Thyroid gland –Hashimoto’s thyroiditis no thyroid hormone production – hypothyroid CD4+ T cells and antibodies against thyroglobulin and microsomal proteins –Graves’ disease Antibodies to TSH receptor – hyperthyroid Negative feedback regulation is not functional CD4+ Th2 cells and antibodies against the muscle of eye – bulding eyes Islets of Langerhans in pancreas –Insulin-dependent diabetes T cells against insulin, glutamic acid decarboxylase GAD –Insulin-resistant diabetes Antagonistic antibodies to insulin receptor Adrenal gland –Addison’s disease – chronic adrenal gland hypofunction Lymphocyte infiltration

13. PITUITARY Tyroid stimulating hormon TSH PITUITARY Tyroid hormons T3/T4 HYPERTYROSIS STIMULATING ANTIBODIES IN GRAVES’ DISEASE Tyroid hormons T3 triiodine tyronin T4 tyroxin Tyroglobulin Folliculus lumen NEGATIVE FEED BACK

14. Nerve impulse Internalization NO Na+ influx NO muscle contraction MIYSTENIA GRAVIS BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS NEURO-MUSCULAR JUNCTION Muscle Acetilcholin receptor

15. Facial, malar "butterfly" rash with characteristic shape across the cheeks. Discoid lupus erythematosus (DLE) involves mainly just the skin, it is relatively benign compared to systemic lupus erythematosus (SLE). In either case, sunlight exposure accentuates this erythematous rash. A small number (5 to 10%) of DLE patients go on to develop SLE (usually the DLE patients with a positive ANA). Here is a more severe inflammatory skin infiltrate in the upper dermis of a patient with SLE in which the basal layer is undergoing vacuolization and dissolution, and there is purpura with RBC's in the upper dermis (which are the reason for the rash). MANIFESTATION OF TYPE III HYPERSENSITIVITY IN SLE