Autoimmune diseases

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

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 PERIPHERAL TISSUES TOLERIZE THEMSELVES PERIPHERAL TOLERANCE IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY

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

DiseaseHLA serotype Relatív riskSex ratio Women/male Ankylosing spondylitisB Acute anterior uveitisB <0.5 Goodpasture’s syndromeDR215.9~1 Multiple sclerosisDR Graves’s diseaseDR Myasthenia gravisDR32.5~1 Systemic lupus erythematosusDR Insulin dependent diabetes mellitus DR3 and DR4 3.2~1 Rheumatoid arthritisDR44.23 Pemphigus vulgarisDR414.4~1 Hashimoto thyroiditisDR ASSOCIATIONS OF HLA ALLOTYPE WITH SUSCEPTIBILITY TO AUTOIMMUNE DISEASE Maximum 20% of predisposed people develop the disease  environmental factors

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

TISSUE-SPECIFIC AUTOIMMUNE DISEASES Endocrine glands I. 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

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

TISSUE-SPECIFIC AUTOIMMUNE DISEASES Endocrine glands II. 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 (21 hydroxilase)

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

Insulin  cell  cell  cell  cell  cell Pancreatic islet cells MECHANISM OF AUTOREACTIVITY IN INSULIN-DEPENDENT DIABETES Type IV hypersensitivity AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING β- CELLS glucagon Somatostatin 10 8 insulin secreting cells

SYSTEMIC AUTOIMMUN DISEASES I. Autoreactivity against common components of human cells Systemic lupus erythematosus SLE –Type III hypersensitivity –Autoantibodies against cell surface, cytoplasmic, nuclear proteins, nucleic acid, nucleoprotein particles induce tissue demage –Comon nucleoprotein particles Nucleosome Splicosome Small cytoplasmic ribonucleoprotein complex – Ro, La –Soluble cellular antigens bind antibodies and form soluble immune complexes – released form dying, dead cells –Immune complexes are deposited to blood vessels,kidneys, joints and other tissues

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

If an immunofluorescence stain with antibody to complement or immunoglobulin is performed, then one can see the brightly fluorescing band along the dermal epidermal junction that indicates immune complex deposits are present. Immunofluorescence staining pattern with antibody to IgG showing evidence for immune complexes at the dermal- epidermal junction. If such a pattern is seen only in skin involved by a rash, then the diagnosis is probably DLE, but if this pattern appears even in skin uninvolved by a rash, then the diagnosis is SLE. DEPOSITION OF IMMUNE COMPLEXES IN THE SKIN OF SLE PATIENTS

One of the feared complications of the rheumatic diseases is renal failure. This is most likely to occur with SLE. Here is a glomerulus in which the capillary loops are markedly pink and thickened such that capillary lumens are hard to see. This is lupus nephritis. Here is a glomerulus with thickened pink capillary loops, the so-called "wire loops", in a patient with lupus nephritis. The surrounding renal tubules are unremarkable. RENAL FAILURE IN RHEUMATIC DISEASES

SYSTEMIC AUTOIMMUN DISEASES II. Rheumatoid arthritis – Type IV hypersensitivity –Cellular response to synovial membrane CD4+ and CD8+ T cells, B cells, plasma cells, neutrophils, macrophages Production of rheuma factors – antibodies to IgG- Fc