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AUTOIMMUNE DISEASES ARPAD LANYI PhD LIKE THE HYPERSENSITIVITY REACTIONS, AUTOIMMUNE DISEASES CAN BE CLASSIFIED ACCORDING TO THE EFFECTOR MECHANISM CAUSING THE DISEASE Type II: Antibody against cell-surface or matrix antigens Type III: Immune-complex diseases Type IV: T-cell-mediated diseases TYPE II AUTOIMMUNE DISEASES Antibody against cell-surface or matrix antigens AUTOIMMUNE/IDIOPATHIC THROMBOCYTOPENIC PURPURA (A/ITP) Autoimmun condition causing platelet destruction General features • Can be chronic (adults) or acute (children, after acut viral infection) • MHC susceptibility genes are associated with chronic ATP (HLA DRB1*0410) • A variety of infectious diseases are associated with ATP (H. pylori, Hepatitis B,C, HIV) • More common in women than in men (3:1) Pathogenesis: • Specific anti-platelet antibodies targeting platelet membrane glycoproteins Usually IgG, but can be IgM or IgA Cross the placenta, neonatal ATP Antigen: platelet glycoprotein IIb-IIIa or Ib-IX complexes • Autoantibodies bind to platelets resulting in clearance of the opsonized platelets by the phagocytic cells (RES) PHAGOCYTE IN ACTION Containing one intact platelet (P) and apparently in the process of phagocytosing another DOI: 10.1056/NEJM197709082971001 AUTOIMMUNE/IDIOPATHIC THROMBOCYTOPENIC PURPURA (A/ITP) Autoimmun condition causing platelet destruction Clinical features: • Thrombocytopenia • Megathrombocytes • Increased numbers of megakaryocytes in the bone marrow • Some patients remain asymptomatic for years • If the number of platelets falls below 109 per liter of blood, severe spontaneous bleeding ensues • Severe mucocutaneous bleeding • Intracranial hemorrhage (rare) THERAPY OF ATP IVIG Saturates Fcγ receptor sites on macrophages, induces increased expression of the inhibitory receptor FcγRIIB, which can contribute to the inhibition of phagocytosis. The abnormally high level of circulating IgG has a generally suppressive effect on immunoglobulin synthesis. Less secere case: oral prednisone, prednisolone Severe case: dexamethasone, methylprednisolone infusion Remove existing antibodies Not recommended except in an emergency Rituximab: monoclonal anti-CD20 Ab Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity CD40/CD40L interaction IDEC131 Thrombopoietin receptor agonists Romiplostim (sc.): thrombopoiesis stimulating Fc-peptide fusion protein Eltrombopag: orallyadministered agent AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) Idiopathic AIHA: 50% Warm-reactive antibodies: limphoproliferative diseases, SLE, RA Cold-reactive antibodies: infections (mycoplasma, viral pneumonia, infectious mononucleosis) Drug-induced (methyldopa, penicillin, ceftriaxone) Alloimmune hemolytic anemia Symptoms: • pallor, fatique • shortness of breath, dizziness, headache, • rapid pulse • jaundice, yellowish color of the skin (increased bilirubin) • splenomegaly AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) Mild cases may not require treatment Treatment: Treat underlying disease, infection Immunosuppressive therapy, corticosteroids Prednisone is thought to decrease monocyte- red cell interactions and decrease autoantibody production. Others: Azathioprine, Cyclophosphamid, Chlorambucil Surgery Prednisone unresponsive patients: splenectomy may be considered. (Pneumococcus vaccine before treatment) Immunotherapy, antibodies IVIG Anti-CD20 (rituximab) Plasmapheresis AUTOIMMUNE NEUTROPENIA • Leukocytes are less susceptible to complement-mediated lysis than erythrocytes. • The main effect of complement fixation on leukocyte surfaces is opsonization. • As the opsonized leukocytes circulate through the spleen they are removed and degraded by the resident macrophages. • Neutropenia: most common in infants and young children Symptoms: • Neutrophils are absent or reduced (less than 1.5X 109/L, or 1500/μl). • Mucocutaneous infections • Elevated IgG, myeloid hyperplasia with diminished number of mature cells Therapy: • Corticosteroids to reduce autoantibody production • Antibiotics to prevent infection • G-CSF Stimulates proliferation and maturation Release mature cells into the bloodstream Stimulates phagocyte function Reduces neutrophil apoptosis Raises levels of soluble FcγRIIIb, sequestering autoantibodies • Splenectomy: opsonized leukocytes survive longer in the circulation (opsonized leukocytes are still functional) • IVIG GOODPASTURE’S SYNDROME • Autoantibodies specific for α3 chain of type IV collagen; basement membranes • Autoantibodies are deposited in the basement membranes of organs • High-pressure filtering of blood by renal glomeruli – most sensitive • Glomerulonephritis: IgG is deposited along the basement membranes of renal glomeruli and renal tubules - inflammatory cells accumulate - kidney failure Blood and protein in the urine, high blood pressure, unexplained swelling of limbs or face • Pulmonary hemorrhage: only smokers shortness of breath - coughing up blood, chest pain, • Strong association with HLA-DRB1*15:01/*04 • Therapy: plasmapheresis, immunosuppression (prednisone, cyclophosphamide) BULLOUS SKIN DISEASES PEMPHIGUS VULGARIS • The most severe and common form of pemphigus • IgG4 autoantibodies against Dsg1 (skin lesion) and Dsg3 (mucosal lesion) • Affects the skin and mucous membranes • Usually begins with painful erosions of the oral mucosa (lasts for several months) • Gradually followed by involvment of the skin • HLA associaton: HLA DR4/14 haplotypes, Dsg3-specific DLA-DR restricted Th2 cells • Patients affected are usually in their fourth to sixth decade of life BULLOUS SKIN DISEASES PEMPHIGUS FOLIACEUS • IgG4 autoantibodies against Dsg1 (EC5 – EC1/EC2 – intramolecular epitope spreading) • Affects skin only, superficial blisters, exfoliative erythroderma • Drug-induced pemphigus: penicillamine Pemphigus foliaceus with large scaly and crusted erosions over the trunk giving a ‘corn flakes’ appearance Pemphigus foliaceus characterised by exfoliative erythroderma DOI: 10.5772/56423 BULLOUS SKIN DISEASES THERAPY • Corticosteroids (prednisone); adjuvant therapy: spearing agents (cyclophosphamide, methotrexate) steroid • The mortality rate has been reduced to less than 10% • Complictions: osteoporosis, diabetes, hypertension, obesity • Patient resistant to steroids: plasmaferesis, IVIG • Rituximab: anti-CD20 mAb Nine months after treatment with rituximab, the patient’s clinical condition remained stable Med J Aust 2008; 189 (5): 289-290. ACUTE RHEUMATIC FEVER Group A streptococci, Steptococcus pyogenes Cross reactivity with self antigens present in heart, joint, kidney (M-protein shows sequence similarity with myosin.) Main symptoms: •Pancarditis, cardiac murmur, mitral valve insufficiency •Polyarthritis (joints become hot, red, swollen) •Sydenham’s chorea •Erythema marginatum (rash) Aschoff body: rheumatic granuloma, fibrinoid necrosis surrounded by Aschoff (multinucleated giant cells)/Anitschkow (enlarged macrophages) cells, infiltrated lymphocytes. However only 3% of all patients with untreated Streptococcal pharingytis develop rheumatic fever. Likely that genetic factors contribute to the development of the disease !!! Association between different HLA class II antigens and RF has been found in several populations (USA: DR4, DR9; South Africa: DR1, DR6, Brazil: DR7, DR53 etc.) Therapy: antibiotics, arthritis: salicylates, NSAID During 2nd world war young recruits treated with pencillin within 10 days of strep throat did not get rheumatic fever. BINDING OF ANTIBODIES TO CELL-SURFACE RECEPTORS CAUSES SEVERAL AUTOIMMUNE DISEASES Receptor agonist antibodies: Mimic the natural ligand and cause the receptor to transduce activating signals in the absence of its ligand Examples of organ- or tissue-specific autoimmune diseases Examples of systemic autoimmune diseases Receptor antagonists antibodies: Do not activate signaling on binding to the receptor and they block the natural ligand from binding to the receptor GRAVES’ DISEASE Production of thyroid hormones (thyroxine (T4), triiodothyronine (T3)) is regulated by thyroidstimulating hormone (TSH). AGONIST autoantibodies specific for the TSH receptor CHRONIC OVERPRODUCTION OF THYROID HORMONES The formation of autoantibodies driven by a CD4+Th2 response Graves’ disease is associated with HLA-DR3 (DR7 seems to be protective) GRAVES’ DISEASE Hyperthyroid condition: • Heat intolerance, rapid heart rate, nervousness, irritability, warm moist skin, weight loss, and enlargement of the thyroid • Graves’ ophthalmopathy Autoantibodies made against a thyroid protein cross-react with an eye-muscle protein. Fibroblast – glycosaminoglycan release – edema • Dermopathy – TSH receptor expressing skin fibroblasts Therapy: • Short-term treatment: methimazole, propylthiouracil: inhibit the production of thyroid hormones (inhibitor of thyroperoxidase). • Long-term treatment: radioactive iodine or surgery - destroy or remove the gland - need for lifelong use of replacement of thyroid hormones MYASTHENIA GRAVIS Severe muscle weakness ANTAGONISTIC autoantibodies bind to the acetylcholine receptors on muscle cells - receptor endocytosis - degradation The loss of cell-surface acetylcholine receptors makes the muscle less sensitive to neuronal stimulation - progressive muscle weakening Early symptoms: droopy eyelids and double vision • With time, other facial muscles weaken and similar effects on chest muscles impair breathing susceptibility to respiratory infections, can even cause death Therapy: • Pyridostigmine: inhibitor of the enzyme cholinesterase, which degrades acetylcholine- increases the capacity of acetylcholine to compete with the autoantibodies • During crises of severe muscle immunosuppressive drugs (azathioprine) Myasthenia gravis is associated with HLA-DR3 weakening: TYPE III AUTOIMMUNE DISEASES Immune-complex diseases SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IgG is made against a wide range of cell-surface and intracellular self antigens that are common to many cell types. The immune complexes formed by these antigens and antibodies are deposited in various tissues, where they cause inflammatory reactions resembling type III hypersensitivity reactions. The deposits can cause glomerulonephritis in the kidneys, arthritis in the joints, and a butterfly-shaped skin rash on the face. SLE is particularly common in women of African or Asian origin, 1 in 500 of whom has the disease. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Initiating event: Loss of T-cell tolerance The antibodies specificities depend on the HLA class II type • HLA-DR3: the greatest susceptibility cytoplasmic ribonucleoprotein complex • - small HLA-DR2: double-stranded DNA • HLA-DR5: spliceosome (nuclear ribonucleoprotein complex) Immune complex deposition - Tissue disruption – Release cellular antigens - Further inflammatory reactions Once an antibody has been made against one component of a particle, that antibody can deliver the particle to cells and facilitate the development of antibodies against the other components. Ever-increasing and uncontrolled destruction can affect every tissue of the body! SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Stroke from blood vessel clots Neuropathia, paralysis Persistent headache, memory loss, confusion Reversible blindness, retinal exudates Mucosal ulcers (oral, vaginal, nose) Photosensitivity, exudative erythema, discoid, butterfly rash Pericarditis, myocarditis, endocarditis, pleuritis, peritonitis, pneumonia Glomerulonephritis, hematuria, proteinuria, Bleeding, nausea, vomiting, diarrhea, Menorrhagia, amenorrhoea, prematurity, spontaneous abortion Hemolytic anemia, thrombosis, thrombocytopenia Arthritis (90%), painfull swollen joints, myalgia Outbreaks of intense inflammation alternate with periods of relative calm. Many patients die of the disease because of failure of vital organs such as the brain or the kidneys. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Deposition of immune complexes in the kidney glomeruli SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) THERAPY No cure is available for SLE but there are many treatments for the disease • Disease-modifying antirheumatic drugs (DMARDs): reduce the incidence of flares (methotrexate, azathioprine) • Corticosteroids (flares) • Cyclophosphamide: glomerulonephritis (other organ-damaging complications) • Chronic pain: NSAID • IVIG TYPE IV AUTOIMMUNE DISEASES T-cell-mediated diseases TYPE 1 DIABETES Selective autoimmune destruction of the insulin-producing cells of the pancreas • T-cell and antibody responses Antigen-specific CD8+T-cells are believed to mediate β-cell destruction CD4+Th1 cells Insulin, glutamic acid decarboxylase, and other specialized proteins of the pancreatic β-cell Insulitis: infiltration of lymphocytes from the islet periphery toward the center Comparison of histological sections of a pancreas from a healthy person and a patient with type 1 diabetes TYPE 1 DIABETES Selective autoimmune destruction of the insulin-producing cells of the pancreas • T-cell and antibody responses Antigen-specific CD8+T-cells are believed to mediate β-cell destruction CD4+Th1 cells Insulin, glutamic acid decarboxylase, and other specialized proteins of the pancreatic β-cell • The β-cells comprise about two-thirds of the islet cells; as they die, the architecture of the islet degenerates. 108 β-cells - disease symptoms do not manifest until years • Disease symptoms usually manifest themselves in childhood or adolescence Polyuria (excessive urination), polydipsia (increased thirst), xerostomia (dry mouth), polyphagia (increased hunger), fatigue, weight loss Diabetic ketoacidosis: xeroderma (dry skin), rapid deep breathing, drowsiness, abdominal pain, vomiting • Treatment: daily injection with synthetic human insulin; (coma, death) Treg cell therapy • Type 1 diabetes principally affects populations of European origin, 1 in 300. DQ2, DQ8 allotypes confer susceptibility to type 1 diabetes. DQ6 allotype confers strong resistance to type 1 diabetes. HASHIMOTO’S DISEASE • Caused by a CD4 Th1 response • Effector CD4+T-cells and antibodies specific for thyroid antigens (thyroglobulin, thyroid peroxidase, TSH receptor, thyroid iodide transporter) • Lymphocytes infiltrate the thyroid, causing a progressive destruction of the thyroid tissue Loss of the capacity to make thyroid hormones - hypothyroid • Ectopic lymphoid tissues: a characteristic feature of Hashimoto’s disease: immune cells infiltrating the thyroid gland become organized into structures - lymphoid neogenesis - driven by lymphotoxin Resembling the typical microanatomy of secondary lymphoid organs (T-cell and B-cell areas, dendritic cells, follicular dendritic cells, macrophages) Not encapsulated, lacks lymphatics HASHIMOTO’S DISEASE • Caused by a CD4 Th1 response • Effector CD4+T-cells and antibodies specific for thyroid antigens (thyroglobulin, thyroid peroxidase, TSH receptor, thyroid iodide transporter) • Lymphocytes infiltrate the thyroid, causing a progressive destruction of the thyroid tissue Loss of the capacity to make thyroid hormones - hypothyroid • Ectopic lymphoid tissues: a characteristic feature of Hashimoto’s disease: immune cells infiltrating the thyroid gland become organized into structures - lymphoid neogenesis - driven by lymphotoxin Resembling the typical microanatomy of secondary lymphoid organs (T-cell and B-cell areas, dendritic cells, follicular dendritic cells, macrophages) Not encapsulated, lacks lymphatics Functions like a secondary lymphoid tissue o T- and B-cells are stimulated by antigen to give effector cells, germinal center reactions: isotype switching, somatic hypermutation HASHIMOTO’S DISEASE Most common symptoms: • Fatigue, weight gain, feeling cold, joint and muscle pain, depression, panic disorder, slowed heart rate, irregular periods, problems getting pregnant and maintaining pregnancy HLA DR4 association (protective: DR13) Treatment: • Replacement therapy with synthetic thyroid hormones taken orally on a daily basis. RHEUMATOID ARTHRITIS The most common rheumatic disease (1–3% in US) • Chronic and episodic inflammation of the joints. • The synovium of an arthritic joint is infiltrated: CD4 and CD8 T-cells, B-cells, lymphoblasts, plasma cells neutrophils, macrophages • Pro-inflammatory cytokines: IFN-γ, IL-17, IL-1 , IL-6, TNF-a • Prostaglandins, leukotrienes, lysosomal enzymes: tissue damage, synoviocyte activation • Fibroblasts activated by cytokines produce matrix metalloproteinases (MMPs), which contribute to tissue destruction. • Proteinases and collagenases: cartilage, ligaments, tendons • The TNF-family cytokine RANK ligand (T-cells, fibroblasts): primary activator of bone-destroying osteoclasts • Rheumatoid factor: IgM, IgG, and IgA antibodies specific for the Fc region of human IgG (80%) • ACPA: HLA DR4, smoking RHEUMATOID ARTHRITIS The most common rheumatic disease (1–3% in US) X-ray of the right hand of a patient with rheumatoid arthritis. It shows extensive destruction and dislocation of the metacarpophalangeal joints. Inflamed joints in the hand of a patient with rheumatoid arthritis RHEUMATOID ARTHRITIS The most common rheumatic disease (1–3% in US) • Rheumatoid arthritis is a chronic, painful, and debilitating disease, which patients can suffer for many decades of their lives (usually starting between 20 and 40 years of age). • Therapy: • Physiotherapy with anti-inflammatory and immunosuppressive drugs, glucosamine, chondroitin • Rituximab: anti-CD20 mAb • Anti-TNF-α antibodies: infliximab (chimeric), adalimumab MULTIPLE SCLEROSIS Pathogenesis of multiple sclerosis • CNS is a relatively immunologically privileged site from which antigens do not normally reach the lymphoid tissues. • In MS, an unknown injurious event is presumed to provoke the release of CNS antigens and their presentation to lymphocytes in the peripheral lymphoid organs. • This results in the expansion of clones of autoreactive T-cells and their differentiation into Th1, Th17 cells, which home to the CNS and initiate inflammation. MULTIPLE SCLEROSIS a4:B1 integrin VCAM Pathogenesis of multiple sclerosis Sclerotic plaques of demyelinated tissue in the white matter of the central nervous system T-cells reencounter antigen: microglia: phagocytic macrophage-like cells of the innate immune system resident in the CNS Inflammation, IFN-γ, IL-17, increased vascular permeability: T -cell, B-cell, macrophage, dendritic cell infiltration, mast cells: histamine Oligoclonal IgG: structural proteins of myelin MULTIPLE SCLEROSIS • A variety of nervous symptoms: Muscle weakness, impaired vision, ataxia, spasticity (excessive contraction of muscles), paralysis of limbs, urinary incontinence • It can alternate between acute attacks of exacerbating disease and periods of gradual recovery. • The disease is 10 times more frequent in women than in men and is associated with HLA-DR2. • Therapy: Regular subcutaneous injection of IFN-β1 reduces the incidence of disease attacks and the appearance of plaques. Disease attacks: immunosuppressive drugs, corticosteroids THANK YOU AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) Idiopathic AIHA: 50% Warm-reactive antibodies: limphoproliferative diseases, SLE, RA Cold-reactive antibodies: infections (mycoplasma, viral pneumonia, infectious mononucleosis) Drug-induced (methyldopa, penicillin,ceftriaxone) Alloimmune hemolytic anemia Symptoms: • pallor, fatique • shortness of breath, dizziness, headache, • rapid pulse • jaundice, yellowish color of the skin (increased bilirubin) • gallstones • splenomegaly ACUTE RHEUMATIC FEVER Group A streptococci, Steptococcus pyogenes Cross reactivity with self antigens present in hart, joint, kidney (M-protein shows sequence similarity with myosin.) Main symptoms: •Pancarditis, cardiac murmur, mitral valve insufficiency •Polyarthritis (joints become hot, red, swollen) •Sydenham’s chorea •Erythema marginatum (rash) Aschoff body: rheumatic granuloma, fibrinoid necrosis surrounded by Aschoff (multinucleated giant cells)/Anitschkow (enlarged macrophages) cells, infiltrated lymphocytes. However only 3% of all patients with untreated Streptococcal pharingytis develop rheumatic fever. Likely that genetic factors contribute to the development of the disease !!! Association between different HLA class II antigens and RF has been found in several populations (USA: DR4, DR9; South Africa: DR1, DR6, Brazil: DR7, DR53 etc.) Therapy: antibiotics, arthritis: salicylates, NSAID During 2nd world war young recruits treated with pencillin within 10 days of strep throat did not get rheumatic fever. GRAVES’ DISEASE Production of thyroid hormones (thyroxine (T4), triiodothyronine (T3)) is regulated by thyroidstimulating hormones (TSH) AGONIST autoantibodies specific for the TSH receptor CHRONIC OVERPRODUCTION OF THYROID HORMONES The formation of autoantibodies driven by a CD4+Th2 response Graves’ disease is associated with HLA-DR3 (DR7 seems to be protective) MULTIPLE SCLEROSIS a4:B1 integrin VCAM Pathogenesis of multiple sclerosis Sclerotic plaques of demyelinated tissue in the white matter of the central nervous system T-cells reencounter antigen: microglia: phagocytic macrophage-like cells of the innate immune system resident in the CNS Inflammation, IFN-γ, IL-17, increased vascular permeability: T -cell, B-cell, macrophage, dendritic cell infiltration, mast cells: histamine Oligoclonal IgG: structural proteins of myelin