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HYPERSENSITIVITY REACTIONS Immune responses that are inadequately controlled, inappropriately targeted to host tissues, or triggered by commensal microorganisms or usually harmless environmental antigens. AN OVERVIEW OF HYPERSENSITIVITY REACTIONS Type I. Type II. „immediate” Type III. Type IV. „late” Antibody mediated T cell mediated Types of antibody mediated hypersensitivity reactions FcRIα) 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 I HYPERSENSITIVITY REACTION ALLERGY Immune responses to nonmicrobial environmental antigens that involve TH2 cells, immunoglobulin E, mast cells, and eosinophils Common allergic symptoms Sequence of events in immediate hypersensitivity reactions TFH Cellular and Molecular Immunology, 7th ed., 2012 Elsevier Sensitization to an inhaled allergen Biochemical events of mast cell activation Effector molecules released by mast cells The physical effects of IgE-mediated mast-cell degranulation vary with the tissue exposed to allergen The acute response in allergic asthma leads to TH2-mediated chronic inflammation of the airways Defense against many helminthic infections is mediated by IgE antibodies and activation of eosinophils Systemic anaphylaxis is caused by allergens that reach the blood stream Normal larynx Laryngeal oedema Genetic/environmental predisposition to allergy Genetic factors chromosome 11q FcεRβ chain gene chromosome 11q IL-3-5 IL-9, IL-13 GMCSF HLAII DRB1*015 Inproper immunregulation Th1/Th2 inbalance regulation of IgE synthesis high eosinophil counts allergy Environmental factors lack of tolerance The wheal and flare reaction in the skin Cellular and Molecular Immunology, 7th ed., 2012 Elsevier Mediators and treatment of asthma Antihistamines Cellular and Molecular Immunology, 7th ed., 2012 Elsevier Monoclonal Anti-IgE • Anti-IgE therapy represents a novel immunomodulatory approach that targets an early point in the allergic inflammatory cascade. • Omalizumab is a recombinant humanized monoclonal anti-IgE antibody TYPE II HYPERSENSITIVITY IgG or IgM antibodies bound to antigens of particular cells or the extracellular matrix Mechanisms of type II hypersensitivity reactions Cellular and Molecular Immunology, 7th ed., 2012 Elsevier Examples of type II hypersensitivity AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) Idiopathic AIHA: 50% Symptoms: Warm-reactive antibodies: limphoproliferative diseases, SLE, RA • pallor, fatique Cold-reactive antibodies: infections (mycoplasma, viral pneumonia, infectious mononucleosis) • rapid pulse Drug-induced (methyldopa, penicillin, ceftriaxone) • splenomegaly Alloimmune hemolytic anemia • shortness of breath, dizziness, headache, • jaundice, yellowish color of the skin (increased bilirubin) AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) Mild cases may not require treatment Treatment: Treat underlying disease, infection Immunosuppressive therapy, corticosteroids Prednisone is thought to decrease monocytered 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 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, cyclophosphamide) immunosuppression (prednisone, 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, Dsg3specific DLA-DR restricted Th2 cells • Patients affected are usually in their fourth to sixth decade of life 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 tissuespecific 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 thyroid-stimulating 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 acetylcholineincreases 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 TYPE III HYPERSENSITIVITY Antibodies form immune complexes in the circulation, and the complexes are subsequently deposited in tissues, particularly in blood vessels, and cause injury Immune complex–mediated tissue injury Cellular and Molecular Immunology, 7th ed., 2012 Elsevier Tissue damage caused by deposited immune complexes Frustrated phagocytosis Immune complexes activate the complement system, neutrophils, basophils and thrombocytes Examples of human immune complex–mediated diseases Symptoms caused by type III hypersensitivity reactions depend on the site of immunecomplex deposition Arthus-reaction • Localized Type III hypersensitivity • Local vasculitis develops as a result of immune complex deposition • Inhaled antigens (fungi, animal feces) may induce similar reaction in the lung (Farmer’s lung and pigeon-breeder’s lung) Localized deposition of immune complexes within a tissue causes a type III hypersensitivity reaction 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) Deposition of immune complexes in the kidney glomeruli TYPE IV HYPERSENSITIVITY REACTION T lymphocytes injure tissues either by triggering inflammation or by directly killing target cells Type IV hypersensitivity reactions Mechanisms of T cell–mediated hypersensitivity reactions Cellular and Molecular Immunology, 7th ed., 2012 Elsevier Tuberculin skin test Introduction of Ag Ag = antigen Purified protein derivate (PPD) Most type IV hypersensitivity reactions are orchestrated by the cytokines released by TH1 CD4 cells in response to antigen DTH as a result of a contact-sensitizing agent* CONTACT DERMATITIS *a contact-sensitizing agent is usually a small molecule that penetrates the skin then binds to self-proteins, making them “look” foreign CONTACT DERMATITIS Poison ivy Anacardiaceae (family), Toxicodendron (genus) Toxicodendron radicans or Rhus toxicodendron Physical contact with poison ivy transfers pentadecacatechol, which causes dermatitis CELIAC DISEASE Delayed-type hypersensitivity 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 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 (Tcell and B-cell areas, dendritic cells, follicular dendritic cells, macrophages) Not encapsulated, lacks lymphatics 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 MULTIPLE SCLEROSIS a4:B1 integrin - VCAM Pathogenesis 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 DEVELOPMENT OF AUTOIMMUNITY CENTRAL AND PERIPHERAL TOLERANCE TO SELF ANTIGENS Central tolerance: Elimination of self-reactive clones. BUT!!! Some clones escape. Peripheral tolerance: Elimination of „fugitive” or altered clones is an important role for regulatory T-cells. 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 UNDER NORMAL CIRCUMSTANCES PERIPHERAL TISSUES ARE PROTECTED FROM IMMUNE RESPONSE SINGLE GENE MUTATIONS CAUSE AUTOIMMUNITY • AIRE - Failure of central tolerance - APECED • FOXP3 – Deficiency of functional regulatory T cells - IPEX • CTLA4 - Failure of anergy in CD4+ T cells; defective function of regulatory T cells - several autoimmune disorders • CD25 - Defective development, survival, or function of regulatory T-cells – IPEX-like • C4 - Defective clearance of immune complexes; failure of B cell tolerance – SLE • FAS/FASL - Defective deletion of anergic selfreactive B cells; reduced deletion of mature CD4+T cells - Autoimmune lymphoproliferative syndrome (ALPS) These genes are associated with rare autoimmune diseases, their identification has provided valuable information about the importance of various molecular pathways in the maintenance of self-tolerance. AUTOIMMUN REGULATOR (AIRE) A transcription factor expressed by thymic medullary epithelial cells and induces expression of many tissuespecific genes Deficiency in establishing central T-cell tolerance allows too many self reactive T-cell clones to leave the thymus AUTOIMMUNE POLYENDOCRINOPATHYCANDIDIASIS-ECTODERMAL DYSTROPHY (APECED) Rare disease, but more frequently seen in inbred populations Finnish, Iranian Jews and in the island of Sardine SYMPTOMS OF APECED • Anti-Th17 specific antibodies!!!!! • Role of Th17 discovered by studying a rare immunodeficiency • https:///jimneydandme MOST AUTOIMMUNE DISEASES ARE COMPLEX POLYGENIC TRAITS MULTIPLE INHERITED GENETIC POLYMORPHISMS CONTRIBUTE TO DISEASE SUSCEPTIBILITY HLA IS THE DOMINANT GENETIC FACTOR AFFECTING SUSCEPTIBILITY TO AUTOIMMUNE DISEASE Family studies reveal that HLA type correlates with susceptibility to type 1 diabetes Haplotype is a group of genes within an organism that was inherited together from a single parent Similar results are seen for many autoimmune diseases ASSOCIATIONS OF HLA ALLOTYPES WITH AUTOIMMUNE DISEASE HLA associations reflect the importance of T-cell tolerance in preventing autoimmunity Many more autoimmune diseases are associated with HLA II than with HLA I indicating that CD4+T-cells are inherently more likely to lose tolerance to a self antigen than are CD8+T-cells GENETIC PREDISPOSITION IS NOT EQUAL TO AUTOIMMUNE DISEASE INDIVIDUALS WITH GENETIC PREDISPOSITION DEVELOP AUTOIMMUNE DISEASE WITH A MAXIMUM FREQUENCY OF 20% ENVIRONMENTAL FACTORS PLAY A ROLE IN DEVELOPING OF AUTOIMMUNITY DRUG INDUCED HEMOLYTIC ANEMIA • Alpha methyldopa therapy results in the formation of red blood cell autoantibodies in 10-20% of patients taking the drug for longer than 4 months. True autoantibodies: directed against an autoantigen on the red blood cell membrane, not against the drug The target membrane antigen is usually within the Rhesus system • Drug-dependent Abs Penicillin, cefotetan: covalently bind to RBC membrane proteins. o Anti-drug Ab (usually IgG) - attaches to the drugcoated RBCs - clearance by macrophages Ceftriaxone: binds non-specifically to RBC membrane proteins o Abs are formed to the combined membrane-drug (hapten) complex, can be IgM or IgG, and often activate complement - acute rapid intravascular hemolysis SMOKING Smoking damages the mucosa of the airways and exacerbates many diseases. All patients with Goodpasture’s syndrome develop glomerulonephritis, but only those who habitually smoke cigarettes develop pulmonary hemorrhage. In nonsmokers, the basement membranes of lung alveoli are inaccessible to antibodies. In smokers the lack of integrity gives circulating antibodies access to the basement membranes. PHYSICAL TRAUMA ROLE OF INFECTIONS IN THE DEVELOPMENT OF AUTOIMMUNITY MOLECULAR MIMICRY MAY LEAD TO SEVERE AUTOIMMUNE REACTIONS BODIES AGAINST STREPTOCOCCAL CELL-WALL ANTI CROSS-REACT WITH ANTIGENS ON HEART TISSUE ROLE OF OTHER INTRINSIC FACTORS IN AUTOIMMUNITY HORMONES Most autoimmune diseases are more prevalent in women than men. Conservative estimates indicate that nearly 80% of individuals with autoimmune diseases are women. Ankylosing spondylitis occurs more frequently in men. SENESCENCE OF THE THYMUS AND THE T-CELL POPULATION CONTRIBUTES TO AUTOIMMUNITY T-cell populations are dynamic: • T-cells must divide periodically to survive. • 1% of the body’s T-cells being replaced each day. Once the thymus can no longer fulfill the demand for naive T-cells, the immune system compensates: • expanding the size of existing T-cell clones • altering the properties of T-cells - make them more resistant to apoptosis; CD28 KIR RA: large clones of expanded autoreactive CD4 T-cells • lack of CD28 • express NK-cell receptors - KIR2DS2 • produce large amounts of IFN-γ • not anergic LOSS OF REGULATION OF AUTOREACTIVE T-CELLS RESULTS IN AUTOIMMUNITY FOXP3 deficiency: IPEX CTLA-4 haploinsufficiency: ) autoimmunity IL-10: severe colitis IL-6 mediated resistance in psoriasis Autoimmunity in Dry Eye: qualitative Treg defect – resistance Th17 cells doi:10.1038/nri2889