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DEVELOPMENT OF AUTOIMMUNITY AUTOIMMUNE REACTIONS • During an autoimmune response, the immune system attacks healthy cells and tissues. • Mechanisms of recognition and effector functions are the same as those acting against pathogens and environmental antigens. • These chronic diseases can be potentially fatal (for example autoimmune type 1 diabetes or pernicious anemia). • They cause serious, progressive inflammatory symptoms and induce tissue damages. • Diseases caused by them require life-long treatments. 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 GENERAL FEATURES OF AUTOIMMUNE DISORDERS Autoimmune diseases may be either systemic or organ specific, depending on the distribution of the autoantigens that are recognized. • Circulating immune complexes – SLE • Autoantibodies or T-cell responses against self antigens with restricted tissue distribution - Type 1 diabetes Various effector mechanisms are responsible for tissue injury in different autoimmune diseases. • Autoantibodies • Immune complexes (self antigen + autoantibody) • Autoreactive T lymphocytes All autoimmune diseases involve breaking T-cell tolerance. AUTOANTIBODY PRODUCTION IS DEPENDENT ON THE AVAILABILITY OF AUTOREACTIVE T-CELLS Practically all autoimmune diseases involve some T-cell defects In the absence of T-cell help autoreactive B-cells are retained in the T-cell zone and die by apoptosis SINGLE GENE MUTATIONS CAUSE AUTOIMMUNITY • AIRE - Failure of central tolerance - APECED AUTOIMMUN REGULATOR (AIRE) A transcription factor expressed by thymic medullary epithelial cells and induces expression of many tissue-specific 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-IL-17 specific antibodies! • Role of Th17 discovered by studying a rare immunodeficiency • https:///jimneydandme.wordp ress.com/james-story SINGLE GENE MUTATIONS CAUSE AUTOIMMUNITY • AIRE - Failure of central tolerance - APECED • FOXP3 – Deficiency of functional regulatory T cells - IPEX FOXP3 DEFICIENCY:IPEX Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome Polyendocrinopathy: multiple disorders of the endocrine glands Type 1 diabetes mellitus (most common) develops within the first few months of life Autoimmune thyroid disease (hypo- or hyperthyroidism) Enteropathy: severe diarrhea, usually the first symptom, failure to thrive Dermatitis Autoimmune blood disorders are common; about half of affected individuals have anemia, thrombocytopenia, neutropenia Most patients with IPEX are males and most of them die within the first 2 years of life without treatment (a few with a milder phenotype have survived into the second or third decade of life) 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 self-reactive 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. 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 COMBINATIONS OF HLA CLASS II ALLOTYPES CONFER SUSCEPTIBILITY TO TYPE 1 DIABETES Common Caucasian HLA haplotypes that encode either the DQ2 or the DQ8 allotype confer susceptibility to type 1 diabetes. Heterozygous individuals are more susceptible to diabetes. This augmented susceptibility is due to a novel HLA-DQ heterodimer consisting of the DQ8 αchain and the DQ2 β-chain. POLYMORPHISMS IN NON-HLA GENES ASSOCIATED WITH AUTOIMMUNITY 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 INFECTIONS: ENVIRONMENTAL FACTORS THAT CAN TRIGGER AUTOIMMUNE DISEASE ROLE OF INFECTIONS IN THE DEVELOPMENT OF AUTOIMMUNITY MOLECULAR MIMICRY MAY LEAD TO SEVERE AUTOIMMUNE REACTIONS INFECTIONS ASSOCIATED WITH THE START OF AUTOIMMUNITY ANTIBODIES AGAINST STREPTOCOCCAL CELL-WALL ANTIGENS CROSS-REACT WITH ANTIGENS ON HEART TISSUE Focal infections • A local chronic infection affecting a small area of the body can lead to subsequent symptoms in other parts of the body due either to the spread of the infectious agent itself or toxins produced from it. A focus of infection may be described as a circumscribed area of tissue infected with pathogenic organisms. • The pathogenesis of focal diseases has been classically attributed to dental infections. • Chronic periodontitis may be a causal factor in the pathogenesis of rheumatoid arthritis. ROLE OF THE GUT MICROBIOTA IN AUTOIMMUNITY doi:10.1038/nri3430 doi:10.1038/nri3430 ROLE OF THE GUT MICROBIOTA IN AUTOIMMUNITY doi:10.1038/nri3430 doi:10.1038/nm0911-1055 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 drug-coated 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 PHYSICAL TRAUMA 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. RHEUMATOID ARTHRITIS IS INFLUENCED BY GENETIC AND ENVIRONMENTAL FACTORS Smoking is the major environmental factor associated with rheumatoid arthritis Smoking, HLA-DR4 and an immune response to citrullinated proteins are all tied together in the same diseasecausing mechanism ACPA+: strong association with HLADR4 and smoking smokers APCA-: no association nonsmokers Basic residues in the peptide-binding groove of the DRβ*04 chain are necessary to confer susceptibility to rheumatoid arthritis GENETIC AND ENVIRONMENTAL FACTORS ACT TOGETHER TO CAUSE AUTOIMMUNITY HORMONES ALSO AFFECT THE DEVELOPMENT OF AUTOIMMUNITY 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. AUTOIMMUNE DISEASES TEND TO BE CHRONIC, PROGRESSIVE AND SELFPERPETUATING Self antigens are persistent, and once an immune response starts, many amplification mechanisms are activated that perpetuate the response Tissue injures result in the release and alterations of other tissue antigens, activation of lymphocytes specific for these other antigens, and exacerbation of the disease MECHANISMS OF CHRONICITY OF AUTOIMMUNE DISEASES INTRAMOLECULAR EPITOPE SPREADING PEMPHIGUS FOLIACEUS INTERMOLECULAR EPITOPE SPREADING IN SLE SIMILARLY TO HYPERSENSITIVITY REACTIONS, AUTOIMMUNE DISEASES CAN ALSO BE GROUPED BY THEIR EFFECTOR MECHANISM