Tolerance and Autoimmunity PDF 2024

Tolerance and Autoimmunity Dr. Abdulrahman Alsultan 03/12/2024  Objectives 1. What I mean by immunological tolerance ? 2. How many type of tolerance? 3. How tolerance is induced? 4. What is the difference between central and peripheral tolerance ? 5. What...

Tolerance and Autoimmunity Dr. Abdulrahman Alsultan 03/12/2024  Objectives 1. What I mean by immunological tolerance ? 2. How many type of tolerance? 3. How tolerance is induced? 4. What is the difference between central and peripheral tolerance ? 5. What is the mechanisms of auto tolerance or how this can lead to auto reactivity ? 6. What is autoimmunity ?  Immunological Tolerance https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcSZGazxA1CKWrTY5f45rIbNWJEmAkVQk8Eh3c-CffGaTG3BQFhm Immunological tolerance is unresponsiveness to self antigens. Lack of response to antigens The immune system does not react against each individual’s own (self) antigens. All individuals are tolerant of unresponsive to their own self antigens It has an ability to discriminate between self and none self antigens. if the mechanisms failed, the immune system may attack the individuals own cells and tissues, this reaction called autoimmunity  Tolerance The immune system able to discriminate between self and noneself antigens Failure of immunological tolerance Autoimmunity Autoimmune diseases Tolerance refers to the specific immunological non-reactivity to an antigen resulting from a previous exposure to the same antigen. There are two types of tolerance: 1. Autotolerance 2. Induced tolerance  Tolerance 1- Autotolerance (self-tolerance, natural tolerance) It is non-reactivity (unresponsiveness) to self antigen. It is the failure of the immune system to attack the body's own proteins and other antigens and it is desired. 2- Induced tolerance: Tolerance to non-self antigens. Tolerance to external antigens that has been created by intentionally manipulating the immune system. When an antigen induces tolerance, it is termed “Tolerogen”.  Tolerance Induction of tolerance to non-self antigens How tolerance is induced? Tolerance can be induced by administering antigen in particular ways, and this strategy may be useful and important. - Tolerance can be induced to antigenic components on both soluble proteins or cells (tissues) by injecting these materials into a host. - Induction of such a tolerance depends on a number of variables.  4 Factors affecting the induction of tolerance 1- Immunologic maturity of the host: Neonates are immunologically immature and easier to be immunologically tolerated and will accept allografts that would be rejected by mature host. 2- Structure and dose of antigen: a- Simple molecules induce tolerance more readily than complex ones. b- Very high and very low doses of antigen may result in tolerance “immune paralysis”. c- Continuous presence of antigen helps to maintain tolerance.  Factors affecting the induction of tolerance 3- Administration of immunosuppressive drugs enhances tolerance e.g. in transplantation. 4- Tolerance is induced by soluble antigens administered either intravenously or orally.  Importance of induced tolerance 1- Protection against allergic reactions due to food (e.g. peanuts), insect stings and pollen grains. 2- Avoidance of graft rejection and to enable transplanted organs to survive in their new host. 3- Some trails are done to use antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. How much immunological tolerance is important ? 1. Treating immunological diseases 2. Treatment of allergy 3. Treatment of autoimmune diseases 4. Prevent rejection 5. Prevention of immune response against newly expressed genes (Gene therapy)  The difference between central and peripheral tolerance 1- Central tolerance : It occurs during development of T and B cells and operates in the thymus and bone marrow. 2- Peripheral tolerance : It is developed after maturation of T and B cells.  Tolerance? Central tolerance: developing lymphocytes encounter these antigens in the generative central lymphoid organs ( during development). Peripheral tolerance : developed after T and B cells being mature and enter in peripheral tissues. Types of Immunological Tolerance to Self Antigens Central Tolerance Peripheral Tolerance Central Lymphoid Organs Peripheral tissues (Bone marrow and thymus) After Maturation During Development  Central and Peripheral tolerance? Central tolerance: Immune lymphocytes specific for self antigens may encounter these antigens in generative lymphoid organs and are deleted : B lymphocyte change their maturation and enter peripheral tissues. Peripheral tolerance : when mature lymphocytes encounter self antigen in peripheral tissues Mature self reactive lymphocytes may be inactivated by encounter with self antigens in peripheral tissues. B lymphocytes are shown in this illustration but general principles apply to T lymphocytes as well.  Mechanisms of autotolerance Self proteins Immature T cells in the thymus Those that bind → die (Apoptosis)  Mechanisms of autotolerance A- Autotolerance of T cells: 1- Clonal deletion (for central tolerance): - Autotolerance is acquired during embryonic life as a result of deletion or killing (negative selection) of self reactive T cell in the thymus. - Autotolerance during exogenous substances injected into the fetus in early development which treated as self.  Mechanisms of autotolerance A- Autotolerance of T cells: 2- Clonal anergy (for peripheral tolerance): - Anergy is a lack of reaction by the body's defense mechanisms to foreign substances. - Clonal anergy occurs outside the thymus and involves functional inactivation of certain T cells. - Clonal anergy may be due to inappropriate presentation of self-antigens, leading to failure of interleukin 2 (IL-2) production.  Mechanisms of autotolerance A- Autotolerance of T cells: 3- Suppressor T cells (regulatory T cells): - They suppress the activity of the immune system and maintain tolerance to self- antigens. - Both low and high doses of antigen may induce suppressor T cells which suppress immune responses of both B and T cells, either directly or by production of cytokines e.g. IL-10 (human cytokine synthesis inhibitor).  Mechanisms of autotolerance B- Autotolerance of B cells: a- Clonal deletion. b- Clonal anergy. c- Suppressor cells. d- Receptor editing: - Receptor editing may lead to changing of the affinity and specificity of B cells due to presence of large amount of soluble antigen.  Autoimmunity What is meant by autoimmune disease? Autoimmunity is an immune response against self antigens. The principal factors in the development of autoimmunity are the inheritance of susceptible genes and environmental triggers (e.g. Infection). It could be as a result in the production of antibodies against antigens or the activation of T cells reactive with self antigens. We still do not know the etiology of any human autoimmune disease  Autoimmunity The exact cause of autoimmune disorders is unknown Multifactorial triggers  Autoimmunity Polygenic MHC genes Genetic various may confer susceptibility to autoimmunity, probably by influencing the maintenance of self tolerance. Environmental triggers such as infection stimuli, promote the influx of lymphocytes into tissues and activation of self – reactive T cells, resulting in tissue injury.  Autoimmunity A. Normal encounter of mature T cells with self antigens presented by resting tissue antigens presenting cells results in perepheral tolerance by anergy or deletion. B. Microp may activate APCs to express costomulators and when these APCs present self antigens the specific T cells will activated. C. Some microbial antigens may cross-react with self antigens NB.Costomulator : is often crucial to the (mimicry). development of an effective immune response ▪ Therefore immune response initiated by the microbes may become directed at self cells and tissues. Autoimmunity  Autoimmunity Infection or Trauma Release of Sequestered Antigens Failure of Self Tolerance Autoimmune Disease Thanks