Transcript 1. dia
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 tissuespecific 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 PERIPHERAL TOLERANCE IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY 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 AUTOIMMUNE DISEASES • 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 predisposition 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 ASSOCIATIONS OF HLA ALLOTYPE WITH SUSCEPTIBILITY TO AUTOIMMUNE DISEASE Disease HLA serotype Relatív risk Sex ratio Women/male Ankylosing spondylitis B27 87.4 0.3 Acute anterior uveitis B27 10.04 <0.5 Goodpasture’s syndrome DR2 15.9 ~1 Multiple sclerosis DR2 4.8 10 Graves’s disease DR3 3.7 4-5 Myasthenia gravis DR3 2.5 ~1 Systemic lupus erythematosus DR3 5.8 10 - 20 DR3 and DR4 3.2 ~1 Rheumatoid arthritis DR4 4.2 3 Pemphigus vulgaris DR4 14.4 ~1 Hashimoto thyroiditis DR5 3.2 4-5 Insulin dependent diabetes mellitus Maximum 20% of predisposed people develop the disease environmental factors Defective central tolerance: Autoimmune 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 STIMULATING ANTIBODIES IN GRAVES’ DISEASE PITUITARY PITUITARY Tyroid stimulating hormon TSH NEGATIVE FEED BACK Tyroid hormons T3 triiodine tyronin T4 tyroxin Tyroglobulin Folliculus lumen HYPERTYROSIS Tyroid hormons T3/T4 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) BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS NEURO-MUSCULAR JUNCTION MYSTENIA GRAVIS Nerve impulse Nerve impulse Acetilcholin receptor Muscle Internalization NO Na+ influx NO muscle contraction MECHANISM OF AUTOREACTIVITY IN INSULIN-DEPENDENT DIABETES Type IV hypersensitivity AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING βCELLS Insulin a cell a cell b cell glucagon b cell 108 insulin secreting cells Pancreatic islet cells d cell d cell Somatostatin 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 MANIFESTATION OF TYPE III HYPERSENSITIVITY IN SLE 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). DEPOSITION OF IMMUNE COMPLEXES IN THE SKIN OF SLE PATIENTS 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 dermalepidermal 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. RENAL FAILURE IN RHEUMATIC DISEASES 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. 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 IgGFc