Tolerance, Autoimmune Disorders PDF

18 Tolerance, Autoimmune disorders ILOs By the end of this lecture, students will be able to  Explain concepts of tolerance to self-antigens  Discuss pathogenesis of autoimmune diseases.  Relate autoimmune reactions to some corresponding clinical conditions. I...

18 Tolerance, Autoimmune disorders ILOs By the end of this lecture, students will be able to  Explain concepts of tolerance to self-antigens  Discuss pathogenesis of autoimmune diseases.  Relate autoimmune reactions to some corresponding clinical conditions. Immunologic Tolerance Immunologic tolerance It is the state of inability of the competent immune system to mount an immune response against a particular antigen. Self-tolerance refers to lack of responsiveness to an individual’s own antigens, and it underlies our ability to live in harmony with our cells and tissues. The mechanisms of self-tolerance can be broadly classified into two groups: central tolerance and peripheral tolerance. Central tolerance; Clonal deletion (apoptosis) of autoreactive T and B lymphocytes, in the thymus or bone marrow. 1 Peripheral tolerance, any autoreactive cells that escape central tolerance and migrate to the periphery will be removed or deactivated by; A. Anergy (irreversible functional inactivation) B. Suppression by mechanisms of action of regulatory T cells (that inhibit lymphocyte activation and effectors mechanisms by secretion of cytokines IL-10) C. Deletion of autoreactive lymphocytes by apoptosis, mutation of apoptosis genes leads to development of autoimmune lymphoproliferative disorders. D. Antigen sequestration; certain tissues as brain, eye and testis sequester their antigens behind blood- tissue barrier to be hidden from autoreactive lymphocytes. Traumatic injury may expose these antigens leading to autoimmune uveitis or orchitis. Autoimmune diseases The immune system normally exists in an equilibrium in which lymphocyte activation, which is required for defense against pathogens, is balanced by the mechanisms of tolerance, which prevent reactions against self-antigens. The underlying cause of autoimmune diseases is the failure of tolerance, which allows immune responses to develop against self-antigens. These responses arise through interaction between abnormal susceptibility genes and environmental triggers (mainly infections). Mechanisms of autoimmunity; A. Failure of self tolerance B. Genetic factors C. Infectious factors A. Failure of self tolerance Inheritance of susceptibility genes which contribute to the breakdown of self-tolerance or regulation of immune responses. 1) Breakdown of T cell anergy by upregulate the expression of costimulatory molecules on APCs resulting in breakdown of anergy and activation of T cells specific for the self-antigens. 2) Failure of T cell mediated suppression (AIDS) 3) Molecular mimicry where a microbe shares amino acid sequence with a self-antigen, then immunological reactions will cross-react the pathogen, and become directed against self- antigen leading to tissue injury with activation of non-tolerant lymphocytes mediating an autoimmune reaction. 2  Best example is rheumatic heart disease, in which antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis. 4) Polyclonal B cell activation, Several microorganisms and their products (e.g. EBV) are capable of causing polyclonal activation of B cells. Some of these stimulated lymphocytes may be autoreactive 5) Release of sequestered self Ags and exposure of hidden epitopes through tissue trauma or inflammatory destruction. e.g. lens crystalline of eye, spermatozoa in testis B. Role of Susceptibility Genes ▪ There is a familial increase of incidence of several autoimmune disease e.g SLE ▪ HLA Alleles are known to be associated with autoimmunity. The most striking of these associations is between ankylosing spondylitis and HLA-B27; individuals who inherit this class I HLA allele have a 100- to 200-fold greater chance. Another example is diabetes mellitus type I. ▪ Genetic defects in the apoptotic pathways that would normally regulate the peripheral or central tolerance have been suggested: ▪ Defective regulatory T-cell development.  Most autoimmune diseases have complex, multigenic patterns of susceptibility and are not attributed to a single gene mutation. C. Role of infection The role of microbial agents particularly Viral infection in precipitating autoimmune diseases through: a- Modification of self antigens b- Cross-reaction if they share cross-reacting epitopes (Molecular Mimicry) c- Resulting necrosis and inflammation can induce:  up-regulation of co-stimulatory molecules  Exposure of hidden antigen or cryptic epitopes. d- Polyclonal activation of lymphocytes 3 Tissue damage in autoimmune disease can be  Type II hypersensitivity reaction e.g. autoimmune hemolytic anemia.  Type III hypersensitivity reaction e.g. SLE, rheumatoid arthritis.  Antireceptor antibodies e.g. Myasthenia gravis. General Features of Autoimmune Diseases Diseases caused by autoimmunity have some important general features. 1. Immune responses may target either cellular or organ specific self-antigens. 2. Chronicity, progressiveness; Autoimmune diseases tend to be chronic, with relapses and remissions, and the damage is often progressive. 3. The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response, and are usually overlapping making classification difficult. 4. Autoimmune diseases present similar symptoms across the more than eighty different types. The appearance and severity of these signs and symptoms depends on the location and type of autoimmune response that occurs. 5. An individual may have more than one autoimmune disease simultaneously, and display symptoms of multiple diseases. 6. Signs and symptoms presented, and the disease itself, can be influenced by various other factors such as age, hormones, and environmental factors. 4 7. There are several organs that are commonly impacted by autoimmune diseases: blood vessels, underlying connective tissues, joints and muscles, red blood cells, skin, and endocrine glands (such as thyroid or pancreas glands). Classification of autoimmune diseases: a- Organ-Specific Autoimmune Diseases, some of the more common organ-specific autoimmune diseases include:  Autoimmune Thyroid Disease, Grave’s disease of thyroid gland and Hashimoto thyroiditis  Type 1 Diabetes Mellitus  Myasthenia gravis b- Systemic Autoimmune Diseases Systemic autoimmune diseases can bring about several different issues, as their effects are felt throughout the body. Examples include:  Systemic Lupus erythematosus  Rheumatoid arthritis  Inflammatory bowel diseases 5