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AUTOIMMUNE DISEASES ARPAD LANYI PhD. LIKE THE HYPERSENSITIVITY REACTIONS, AUTOIMMUNE DISEASES CAN BE CLASSIFIED ACCORDING TO THE EFFECTOR MECHANISM CAUSING.

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Presentation on theme: "AUTOIMMUNE DISEASES ARPAD LANYI PhD. LIKE THE HYPERSENSITIVITY REACTIONS, AUTOIMMUNE DISEASES CAN BE CLASSIFIED ACCORDING TO THE EFFECTOR MECHANISM CAUSING."— Presentation transcript:

1 AUTOIMMUNE DISEASES ARPAD LANYI PhD

2 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

3 TYPE II AUTOIMMUNE DISEASES Antibody against cell-surface or matrix antigens

4 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)

5 DOI: 10.1056/NEJM197709082971001 PHAGOCYTE IN ACTION Containing one intact platelet (P) and apparently in the process of phagocytosing another

6 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 10 9 per liter of blood, severe spontaneous bleeding ensues Severe mucocutaneous bleeding Intracranial hemorrhage (rare) AUTOIMMUNE/IDIOPATHIC THROMBOCYTOPENIC PURPURA (A/ITP) Autoimmun condition causing platelet destruction

7 Rituximab: monoclonal anti-CD20 Ab Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity The abnormally high level of circulating IgG has a generally suppressive effect on immunoglobulin synthesis. THERAPY OF ATP Not recommended except in an emergency Thrombopoietin receptor agonists Romiplostim (sc.): thrombopoiesis stimulating Fc-peptide fusion protein Eltrombopag: orally- administered agent IVIG Saturates Fcγ receptor sites on macrophages, induces increased expression of the inhibitory receptor FcγRIIB, which can contribute to the inhibition of phagocytosis. Less secere case: oral prednisone, prednisolone Severe case: dexamethasone, methylprednisolone infusion CD40/CD40L interaction IDEC131 Remove existing antibodies

8 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

9 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

10 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 10 9 /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 AUTOIMMUNE NEUTROPENIA

11 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 - coughing up blood, chest pain, shortness of breath Strong association with HLA-DRB1*15:01/*04 Therapy: plasmapheresis, immunosuppression (prednisone, cyclophosphamide)

12 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

13 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 DOI: 10.5772/56423 Pemphigus foliaceus characterised by exfoliative erythroderma Pemphigus foliaceus with large scaly and crusted erosions over the trunk giving a ‘corn flakes’ appearance

14 BULLOUS SKIN DISEASES THERAPY Corticosteroids (prednisone); adjuvant therapy: steroid spearing agents (cyclophosphamide, methotrexate) 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 Med J Aust 2008; 189 (5): 289-290. Nine months after treatment with rituximab, the patient’s clinical condition remained stable

15 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.

16 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 Mimic the natural ligand and cause the receptor to transduce activating signals in the absence of its ligand Receptor antagonists antibodies: Do not activate signaling on binding to the receptor and they block the natural ligand from binding to the receptor Examples of systemic autoimmune diseases Examples of Examples of organ- or tissue-specific autoimmune diseases

17 CHRONIC OVERPRODUCTION OF THYROID HORMONES Production of thyroid hormones (thyroxine (T4), triiodothyronine (T3)) is regulated by thyroid- stimulating hormone (TSH). AGONIST autoantibodies specific for the TSH receptor The formation of autoantibodies driven by a CD4+Th2 response Graves’ disease is associated with HLA-DR3 (DR7 seems to be protective) GRAVES’ DISEASE

18 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

19 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 weakening: immunosuppressive drugs (azathioprine) Myasthenia gravis is associated with HLA-DR3

20 TYPE III AUTOIMMUNE DISEASES Immune-complex diseases

21 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)

22 The antibodies specificities depend on the HLA class II type HLA-DR3: the greatest susceptibility - small cytoplasmic ribonucleoprotein complex HLA-DR2: double-stranded DNA HLA-DR5: spliceosome (nuclear ribonucleoprotein complex) Initiating event: Loss of T-cell tolerance 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!

23 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)

24 Deposition of immune complexes in the kidney glomeruli SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

25 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 THERAPY SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

26 TYPE IV AUTOIMMUNE DISEASES T-cell-mediated diseases

27 TYPE 1 DIABETES 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 Selective autoimmune destruction of the insulin-producing cells of the pancreas Comparison of histological sections of a pancreas from a healthy person and a patient with type 1 diabetes Insulitis: infiltration of lymphocytes from the islet periphery toward the center

28 TYPE 1 DIABETES 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.  10 8 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. Selective autoimmune destruction of the insulin-producing cells of the pancreas

29 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

30 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

31 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.

32 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

33 Inflamed joints in the hand of a patient with rheumatoid arthritis X-ray of the right hand of a patient with rheumatoid arthritis. It shows extensive destruction and dislocation of the metacarpophalangeal joints. RHEUMATOID ARTHRITIS The most common rheumatic disease (1–3% in US)

34 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 RHEUMATOID ARTHRITIS The most common rheumatic disease (1–3% in US)

35 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 Pathogenesis of multiple sclerosis

36 MULTIPLE SCLEROSIS Pathogenesis of multiple sclerosis a4:B1 integrin - VCAM 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 Sclerotic plaques of demyelinated tissue in the white matter of the central nervous system

37 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

38 THANK YOU

39 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

40 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.

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42 CHRONIC OVERPRODUCTION OF THYROID HORMONES Production of thyroid hormones (thyroxine (T4), triiodothyronine (T3)) is regulated by thyroid- stimulating hormones (TSH) AGONIST autoantibodies specific for the TSH receptor The formation of autoantibodies driven by a CD4+Th2 response Graves’ disease is associated with HLA-DR3 (DR7 seems to be protective) GRAVES’ DISEASE

43 MULTIPLE SCLEROSIS Pathogenesis of multiple sclerosis a4:B1 integrin - VCAM 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 Sclerotic plaques of demyelinated tissue in the white matter of the central nervous system


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