Immunological tolerance is a state of unresponsiveness to antigens that an individual has previously been exposed to. Self-tolerance prevents immune responses against self-antigens. Central tolerance occurs in the thymus and bone marrow and deletes self-reactive immune cells, while peripheral tolerance maintains self-tolerance in tissues through mechanisms like clonal anergy and suppression. Autoimmunity results from a failure of tolerance, allowing immune responses against self-antigens, which can be caused by molecular mimicry, hidden self-antigens becoming exposed, genetic factors, infections, or defects in antigen processing or lymphocyte development.
Immunological tolerance is a state of unresponsiveness to antigens that an individual has previously been exposed to. Self-tolerance prevents immune responses against self-antigens. Central tolerance occurs in the thymus and bone marrow and deletes self-reactive immune cells, while peripheral tolerance maintains self-tolerance in tissues through mechanisms like clonal anergy and suppression. Autoimmunity results from a failure of tolerance, allowing immune responses against self-antigens, which can be caused by molecular mimicry, hidden self-antigens becoming exposed, genetic factors, infections, or defects in antigen processing or lymphocyte development.
Immunological tolerance is a state of unresponsiveness to antigens that an individual has previously been exposed to. Self-tolerance prevents immune responses against self-antigens. Central tolerance occurs in the thymus and bone marrow and deletes self-reactive immune cells, while peripheral tolerance maintains self-tolerance in tissues through mechanisms like clonal anergy and suppression. Autoimmunity results from a failure of tolerance, allowing immune responses against self-antigens, which can be caused by molecular mimicry, hidden self-antigens becoming exposed, genetic factors, infections, or defects in antigen processing or lymphocyte development.
Immunological tolerance is a state of unresponsiveness to antigens that an individual has previously been exposed to. Self-tolerance prevents immune responses against self-antigens. Central tolerance occurs in the thymus and bone marrow and deletes self-reactive immune cells, while peripheral tolerance maintains self-tolerance in tissues through mechanisms like clonal anergy and suppression. Autoimmunity results from a failure of tolerance, allowing immune responses against self-antigens, which can be caused by molecular mimicry, hidden self-antigens becoming exposed, genetic factors, infections, or defects in antigen processing or lymphocyte development.
TOLERANCE AND AUTOIMMUNITY immunological tolerance
Immunological tolerance is a state
of unresponsiveness to a particular antigen to which a person has been exposed earlier. The important aspect of tolerance is self-tolerance, which prevents the body from mounting an immune response against self-antigens. the immune cells (lymphocytes) possess vast diversities of antigen receptors, some receptors may be self-reactive. Traub introduced the first evidence of self-tolerance in 1938, who inoculated mice, in utero, with lymphocytic choriomeningitis virus producing infection and maintained it throughout life. These inoculated mice, unlike normal mice did not produce neutralizing antibodies against the virus. Tolerance could be induced, if some foreign antigens are administered during embryonic life and also in neonates. The key factor determining the tolerance is not the developmental stage, but the state of maturity of the immune cells (lymphocytes) at the time of the encounter of the antigen. In unborn and neonates, the immune cells are still to mature and therefore, the individual remains unresponsive at this stage. Immunological tolerance classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc). Central tolerance is established by deletion of lymphocytes in primary lymphoid organs (thymus for T cells and bone marrow for B cells) if they possess receptors that can react with self antigens or by the emergence of regulatory T cells that can inhibit self- reactive cells. Anergy is a lack of reaction by the body's defense mechanisms to foreign substances and consists of a direct induction of peripheral lymphocyte tolerance peripheral tolerance mechanisms - Colonal ignorance. The self-reactive lymphocyte is present in the periphery, but does not see the antigen it is directed against Immune- privileged sites:- • brain • eyes • testes • placenta, and fetus Control of T-cell trafficking to tissues. Naive cells recirculate through secondary lymphatic organs and bloodstream, but do not enter into tissues under normal conditions. • Sites with immune privilege are anatomical regions that are naturally less subject to immune responses than most other areas of the body. • Immune-privileged sites include the central nervous system and brain, the eyes and the testes - Clonal anergy Full activation of T cells requires co-stimulation through CD28 in addition to TCR ligation. TCR ligation in the absence of co-stimulation leads to an inability to express effector functions like cytokine secretion and makes the cell unresponsive to further stimulation. Control of the expression of the costimulatory molecules CD80 and CD86 (B7) is a major mechanism of peripheral tolerance . - T cell suppression. AUTOIMMUNITY The term autoimmunity refers to a failure of the body’s immune system to recognize its own cells and tissues as “self”, Instead immune responses are launched against these cells and tissues as if they were foreign or invading bodies. It occurs when mechanism of self-tolerance fail. Mechanisms of autoimmunity *Ag released from hidden location. *Antigen generated by molecular changes. *Molecular mimicry. *Alteration in Ag processing. *Infection. *Genetic factors.
Molecular mimicry - the structural similarity between foreign (microbial)
and self-molecules of the mammalian host. Mechanisms of autoimmunity *Lymphocytes abnormalities.
*Failure of central tolerance.
*Overcome of peripheral tolerance.
*Polyclonal lymphocytes activation.
Ag related from hidden location Many self Ag are found in hidden location eg. TESTES ,EYE (CORNEA) organ damage
1. Hidden Ag released 2. Reaches blood stream 3 . Encounter Ag sensitive cells 4. Stimulate autoimmunity Antigen generated by molecular changes Development of completely new epitopes on normal protein. 1. Ab + Ag .
2. New epitopes exposed on Fc region of Ab.
3. Establishment of diseases like rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic (long-lasting) autoimmune disease that mostly affects joints. RA occurs when the immune system, which normally helps protect the body from infection and disease, attacks its own tissues. The disease causes pain, swelling, stiffness, and loss of function in joints. Molecular mimicry
1. Sharing of epitopes between an infectious agent
and its host. 2. Antibodies directed against the infections. 3. Agents start reacting with their normal self Ag. 4. Triggers autoimmunity. Alteration in Ag processing
1. T cell may fail to develop tolerance to an self
Ag simply because it is not efficiently procured. 2. If Something happens to improve the processing, an autoimmune disease may be triggered. 3.This usually happens at the site of inflamation resulting in modified Ab. eg. Thyrotoxicosis , Diabetese. • Infection Autoimmunity is not due to infectious agent itself ,but results from dis- regulation of host immune response by the microbes. This may be due to : *Polyclonal lymphocyte activation. * Enhanced stimulation of co-stimulator. *Alteration of self-Ag (cross-reactive neo-Ag). Example: papillomavirus (HPV) and insulin receptor. GENETIC FACTORS The important genes that regulate the development of autoimmunity are located within MHC. *MHC have got critical role in maturation of T cell . *MHC ll genes are directly responsible for auto antigen processing and presentation. *The structure of Ag binding groove will determine , if specific Ag will trigger an AU response. Lymphocytes abnormalities * Primary abnormalities either in B cell or T cell. Since these cells are critical regulators of all.
* MHC presentation of all antigenic peptide to
these cells will be defective, in case the cells are abnormal.
* Abnormalities in lymphocytes could affect any
one of the mechanism that normally maintains self tolerance. Failure of central tolerance starts AU diseases. Refrences - Textbook of Immunology(Second Edition-2014). Sunil Kumar Mohanty &K Sai Leela. - Oxford Handbook of Clinical Immunology and Allergy(Third edition-2013). Gavin P Spickett. THANK YOU
