Tolerance and Autoimmunity Lectures 2024-2025 PDF

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer...

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer Doctor explanation Abbreviation Key information Book >> >> Zainab Adel Alali Mohamme Abbas Alabdrabalnabi Student explaintion 221-222-223 notes References Deleted Tolerance and Autoimmunity Dr. Abdulrahman Alsultan 03/12/2024  Objectivs 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 Under normal conditions”tolerance”: the immune antigens ‫الجهاز المناعي يغض النظر عن‬ system does not attack self-antigens; it only targets foreign antigens. Under abnormal conditions”autoimmunity”: the immune system attacks self-antigens due to a malfunction, which can be caused by genetic factors or infections, As a result, the immune system starts attacking self-antigens. 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 There is a lot of disease that we don’t know the cause for it, because of autoimmunity.  Tolerance The immune system able to discriminate between self and noneself antigens Failure of immunological tolerance Autoimmunity Most common autoimmune disease is Autoimmune diseases diabetes type 1, when your immune system attack the beta cell which is essential for the production of insulin. 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 the immune system maintains towards self-antigens process of teaching the immune system to recognize specific antigens as non- ‫ ا‬We will stimulate the immune system to produce tolerance threatening 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. In organ transplantation, the transplanted organ is a non-self antigen, so we induce the immune system to produce induced tolerance to prevent it from attacking the new organ and allow it to be accepted by 2- Induced tolerance: the body 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”.  Autotolerance Induced tolerance: It is non-reactivity (unresponsiveness) Tolerance to non-self antigens. to self antigen. Tolerance to external antigens that has been created by intentionally It is the failure of the immune system to manipulating the immune system. attack the body's own proteins and When an antigen induces tolerance, other antigens and it is desired 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 When does the body accept a transplanted organ more easily? when the immune system is immature, such as in young children, weakened, as in cases of immunosuppression. Performing an organ transplant in a child can be more favorable than in an adult because the immune system in children is less mature, which reduces the 1- Immunologic maturity of the host: likelihood of rejecting the transplanted organ. 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. People who receive an organ transplant, such as a liver, need to take immunosuppressive drugs for there whole life.  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. intravenously will be better because it is faster.  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 Important slide occurs : during the early development of T and B cells location: primary lymphoid organs (thymus for T cells and bone marrow for B cells). The importance: It ensures that immune cells do not react to self-antigens. 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. occurs : after T and B cells mature and leave the primary lymphoid organs. location: in secondary lymphoid organs, (such as: Lymph nodes , Spleen)Peripheral tissues The importance: acts as a safeguard to prevent mature immune cells from attacking self- tissues, especially if they escaped central tolerance.  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.  Central and Peripheral tolerance? Central tolerance 1. In primary lymphoid organs: Thymus for T lymphocytes. Bone marrow for B lymphocytes. 2. Self-reactive lymphocytes encounter self-antigens in these organs. 3. Outcomes: Deletion (apoptosis): Self-reactive lymphocytes are destroyed. Receptor editing (in B cells): B cells modify their receptors to reduce self-reactivity. Development of regulatory T lymphocytes (CD4+ T cells only) eliminate self-reactive T cells in the thymus to prevent autoimmune responses and ensure self-tolerance. periphral tolerance 1-In sacondry lymphoid organs or peripheral tissues. 2. Mature lymphocytes encounter self-antigens 3. Outcomes: Inactivation (anergy): They become functionally inactive. Suppression: Regulatory T cells suppress their activity. Deletion (apoptosis): They are eliminated.  Mechanisms of autotolerance Self proteins Immature T cells in the thymus Mechanisms of Autotolerance 1. Immature T cells in the thymus are exposed to self-proteins. 2. Selection process: T cells that do not bind to self-proteins become self-tolerant and survive. T cells that strongly bind to self-proteins are eliminated through apoptosis. 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). In chemotherapy treatment, IL-10 is used to suppress the immune response, allowing the body to better tolerate the chemotherapy  Mechanisms of autotolerance B- Autotolerance of B cells: a- Clonal deletion. b- Clonal anergy. c- Suppressor cells. Receptor editing is a critical step because it provides B cells a "second chance" to avoid self-reactivity before the cell go d- Receptor editing: apoptosis. - Receptor editing may lead to changing of the affinity and specificity of B cells due to presence of large amount of soluble antigen.  Mechanisms of autotolerance B cell T cell Clonal deletion (for central tolerance): - it is acquired during embryonic life - during exogenous substances injected into the fetus in early development Receptor editing: Clonal anergy (for peripheral tolerance): - Receptor editing may - Anergy : is a lack of reaction by the body's defense mechanisms to foreign substances. lead to changing of the - Clonal anergy occurs outside the thymus and involves functional inactivation of certain T cells. affinity and specificity of - Clonal anergy may be due to inappropriate presentation of self-antigens, leading to failure of B cells due to presence interleukin 2 (IL-2) production. of large amount of soluble antigen. - 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).  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 In diabetes, the immune system attacks the beta cells in the pancreas, resulting in insufficient production of insulin. The exact reason for this immune response is still unknown.  Autoimmunity The exact cause of autoimmune disorders is unknown Multifactorial For example: triggers infection and Trauma can damage cells, and these damaged cells may be perceived as foreign or rejected by the immune system. This can lead to an autoimmune response.  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.  Costimulatory molecules like CD80 are essential for the full activation of T cells, Here's how it works and how infections might lead to attacking self-antigens: Role of Costimulatory Molecules (e.g., CD80) Normal T-Cell Activation: Antigen-presenting cells (APCs) like dendritic cells present antigens on their MHC molecules to T cells. However, this is not enough to fully activate T cells. They also require a second signal, provided by costimulatory molecules like CD80/CD86 on the APC binding to CD28 on the T cell. This second signal ensures that T cells are only activated in the presence of "danger signals" (e.g., infection or injury). Infections and Upregulation of Costimulatory Molecules: During infections, pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) stimulate APCs through Toll-like receptors (TLRs). This activation causes dendritic cells to upregulate costimulatory molecules (CD80) and release inflammatory cytokines to activate T cells. What Happens When This Goes Wrong? Some infections or inflammatory conditions can cause abnormal activation of APCs, leading to: Costimulatory molecules binding to T cells that recognize self-antigens. T cells attacking the body’s own tissues, resulting in autoimmune disease. Loss of Tolerance: If resting T cells (that should be tolerant to self-antigens) receive strong costimulatory signals from activated APCs, they may mistakenly attack self-tissues. Additional details for clarification  During a Streptococcus infection, the immune system produces Autoimmunity antibodies to fight the bacteria. some of these antibodies can cross-react with heart tissue due to structural similarities like M protein. This can lead to an autoimmune response, causing rheumatic fever.  Autoimmunity Infection or Trauma Release of Sequestered Antigens Failure of Self Tolerance Autoimmune Disease  team Wishes you the best