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AUTOIMMUNE DISEASES
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AUTOIMMUNITY Autoimmune disease occurs when a specific adaptive immune response is reacted against self antigens. In humans, autoimmunity usually arises spontaneously; that is, we do not know what events initiate the immune response to self that leads to the autoimmune disease.
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Immune tolerance Immune tolerance or immunological tolerance, or immunotolerance, describes a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response.
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Tolerance Central tolerance – deleting T or B clones before maturity if they have receptors that recognize self- antigens with great affinity Peripheral tolerance – kills lymphocytes in secondary lymphoid tissue Also, life span of lymphocytes regulated by apoptosis
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Development of Autoimmune Disease
Autoimmune disease occurs as a result of breakdown in tolerance to self Autoimmune disease is characterized by immune system “attack” against self antigens that lead to tissue damage The attack can be either humoral (by auto- antibodies) or cellular (by auto-reactive T cells). The attack can be directed either against a very specific tissue, or to a large number of tissues (systemic autoimmune disease), depending on the self-antigen which is attacked.
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Molecular Mechanisms of Autoimmunity
Cross-reactivity (Molecular and Viral Mimicry) Viral and nonviral peptides can mimic self-peptides and induce autoimmunity Example: papilloma virus (HPV) and insulin receptor
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Cross-Reactivity
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Molecular Mechanisms of Autoimmunity
Release of Sequestered Antigen Antibodies in blood can attack Myelin Basic Protein if Blood- Brain barrier is breached.
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Molecular Mechanisms of Autoimmunity
Inappropriate MHC expression Type I Diabetes: Pancreatic β cells express abnormally high levels of MHC I and MHC II (?) MHC II – APC only! This may hypersensitize TH cells to β cell peptides.
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Molecular Mechanisms of Autoimmunity
Polyclonal B Cell Activation by Viruses and Bacteria If B cells reactive to self-peptides are activated, autoimmunity can occur. Example: Epstein-Barr Virus, which is the cause of infectious mononucleosis.
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Autoimmune diseases Specific:
Juvenile diabetes (attacks insulin-producing cells) Multiple sclerosis (attacks myelin coating of nerve axons) Myasthenia gravis (attacks nerve-muscle junction) Thyroiditis (attacks the thyroid) … Systemic: Immune complexes accumulate in many tissues and cause inflammation and damage. Systemic Lupus Erythematosus (anti-nuclear antibodies): harms kidneys, heart, brain, lungs, skin… Rheumatoid Arthritis (anti-IgG antibodies): joints, hearts, lungs, nervous system… Rheumatic fever: cross-reaction between antibodies to streptococcus and auto-antibodies.
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SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Chronic systemic autoimmune disease Cause unknown Affects almost any organ(s) Characterized by chronic inflammation
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SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Auto-antibodies formed against variety of self antigens Anti-double stranded DNA,RNA and histones Antibodies against cell surface antigens on RBC’s and/or platelets Tissue damage caused by Type III hypersensitivity reactions Immune circulating complexes formed against self deposit on tissues Vasculitis, synovitis, glomerulonephritis
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Systemic lupus erythematosis is the most commonly known autoimmune disorder. This characteristic “butterfly” rash is made worse by exposure to sunlight. Lupus is a potentially fatal autoimmune disease that strikes 1 in 2,000 Americans and 10 times as many women as men.
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Rheumatoid Arthritis Systemic autoimmune disease
Genetic factors (HLA-DR1, HLA- DR4) Autoreactive B-cells synthesize auto antibody against Fc portion of IgG Rheumatoid factor (RF) Chronic inflammation of synovial joints Proliferation of synovial lining cells Erosion of articular cartilage and adjacent bone
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Rheumatoid arthritis (RA) affects peripheral joints and may cause destruction of both cartilage and bone. The disease affects mainly individuals carrying the DR4 variant of MHC genes. This fact can lead to better prognoses and in aiding efforts to change immune reactions that involve the DR4 variant while leaving other reactions intact.
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Hemolytic Anemia - results from monoclonal antibodies to normal RBC constituents - antibodies coat the erythrocytes, causing clumping, lysis, and premature clearance by the spleen - can be induced by an “offending” agent (parasite, drug, or toxin) that adheres to the RBC - Drug-induced Hemolytic Anemia- drug binds to RBC’s and causes them to become antigenic - antibodies that develop from the drug recognize these cells and they are lysed
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