Tolerance and Autoimmunity
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Tolerance and Autoimmunity

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Tolerance and Autoimmunity Tolerance and Autoimmunity Document Transcript

  • Immunology 4 - Tolerance and Autoimmunity Anil Chopra 1. To understand the concept of immunological tolerance 2. To understand the mechanisms underlying immunological tolerance 3. To understand how defects in tolerance lead to autoimmune disease There are over 70 chronic autoimmune diseases affecting 5-8% of the population (80% of which are women). The major ones are: - Rheumatoid Arthritis: 2.1 million cases 30-50,000 children, 2.1 million lost workdays - Type I diabetes: 300-500,000 cases, (123,000< 20yrs old) - Multiple Sclerosis: 250-300,000 cases (25,000 hospitalisations) - Systemic Lupus Erythematosus (SLE): 240,000 cases - Inflammatory Bowel Disease (IBD): including Crohn’s disease and ulcerative colitis)> 800,000 cases - Autoimmune thyroid disease (ATD): including Hashimoto’s and Grave’s disease: 3.5 cases/ 1000 women, 0.8 cases per 1000 men. - They are caused by the production of antibodies and the induction of an immune response to auto-antigens: • Antibody response to cellular or matrix antigen (Type II) • Immune complex formed by antibody against soluble antigen (Type III) • T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)
  • Immune Response Antigens are presented to T-cells by MHC (major histocompatibility complex) antigen presenting cells. The development of autoimmune disease can be increased by genetics. The different alleles that code for the production of HLA antigens can increase or decrease the risk of development of autoimmune diseases. Syndrome Autoantigen Pathology Insulin dependent diabetes Pancreatic β-cell antigen β-cell destruction mellitus Rheumatoid arthritis Unknown synovial joint antigen Joint inflammation and destruction Multiple Sclerosis Experimental Myelin Basic Protein Brain invasion by CD4+ T-cells, autoimmune encephalitis (EAE) Proteolipid protein (demyelination), weakness Myelin Oligodendrocyte glycoprotein B-cells, T-cell and NK cells all have a role in autoimmune disease.
  • Protective Mechanisms It has been shown that we are tolerant (unable to respond) to self antigens but this tolerance decreases with age and is specific. The tolerance is: • Acquired -involves cells of the acquired immune system and is ‘learned’. • Antigen specific • Active process in neonates the effects of which are maintained throughout life. There are a number of mechanisms in tolerance of which any can fail resulting in an autoimmune disease: Central Tolerance T-cells: Because T-cells are produce in the bone marrow but don’t mature until the get to the thymus, they can only become selective after reaching the thymus. The thymus presents the antigens on dendritic or thymic epithelial cells which then bind to immature T-cells forming a pool of immature T-cells. Only 5% of the mature T-cells in the thymus undergo positive selection and clonal expansion. These cells will be restricted from self MHC molecules and hence will be self tolerant. T- Cell repertoire before selection Negative Neglect Selection 5% 90% Apoptosis Positive Apoptosis 5% Selection Export to Periphery Self MHC restricted, Self Tolerant, T-cell repertoire with ability to respond to pathogens Those T-cells which have a high affinity for self antigen MHC-complexes are destroyed by apoptosis. Selection depends on the affinity of peptide antigen MHC complex: TCR interaction and mount of peptide-MHC complex.
  • B-cells: tolerance occurs in the bone marrow by the deletion of immature B-cells when cross-linking of the immunoglobulins on the surface of the cells. If central tolerance fails, then a condition called APECED results: Autoimmune Polyendocrinopathy- Candidiasis- Ectodermal Dystrophy (auto-immune polyglandular syndrome type 1) It is a rare autoimmune disease that affects all endocrine glands (thyroid, kidneys, pancreas-diabetes, gonadal failure, pernicious anaemia). It is caused by mutation of the AIRE gene which is responsible for presenting antigens to T-cells in the thymus. Most autoimmune diseases affect multi-organ systems: e.g. SLE (systemic lupus erythematosis). In SLE autoantibodies are generated against a range of broad spectrum antigens. Immune complexes activate forming deposits and causing tissue damage in a wide range of tissues.
  • Peripheral Tolerance Many antigens are not expressed until the immune system has matured so in order to prevent immune responses, 4 mechanisms are in place: Anergy: in order for naive T-cells to produce an immune response, they need to be co-stimulated, however most cells in the body do not have the ability to do this. B Cells’ anergy is induced by high concentrations of soluble antigen resulting in down-regulation of surface immunoglobulins. Split Tolerance: this results from the fact that in order to induce an immune response, B-cells need to be activated by T-cells. B-cells often persist in an inactive state. Ignorance: this occurs when antigenic concentration is too low in the periphery or when there is no antigen presentation (no MHC II). There are also some immunologically privileged sites where immune cells cannot normally penetrate: for example in the eye, central and peripheral nervous system and testes. In this case cells have never been tolerised against the autoantigens. - following surgery or infection sympathetic Uveitis can develop. This leads to an immune cells filtering into one eye, and hence an immure response attacking the other eye. Suppression: Autoreactive T-cells may be present but do not respond to auto-antigen because of other cell types resulting in negative signalling. Failure in peripheral tolerance can result in IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome) - a fatal recessive disorder presenting early in childhood. It is caused by a mutation in the FOXP3 gene which encodes a transcription factor ‘scurfy’, critical for the development of regulatory T-cells. Symptoms include: • early onset insulin dependent diabetes mellitus • severe enteropathy • eczema • variable autoimmune phenomena • severe infections