Immunological Tolerance PDF

Immunological Tolerance Name: Dr. Nadeem Ikram Title: Assistant Professor of Immunology Department: Microbiology Learning outcome of the session At the end of the lecture the students should be able to: Define Tolerance Explain the mechanism of central and peripheral tolerance of T and B cel...

Immunological Tolerance Name: Dr. Nadeem Ikram Title: Assistant Professor of Immunology Department: Microbiology Learning outcome of the session At the end of the lecture the students should be able to: Define Tolerance Explain the mechanism of central and peripheral tolerance of T and B cells Discuss the process of anergy, deletion, immune suppression, privileged sites Outline Definition Autoimmunity and autoimmune disease Tolerance Central tolerance of T lymphocytes Peripheral tolerance of T lymphocytes Central tolerance of B lymphocytes Peripheral tolerance of B lymphocytes Pathogenesis of autoimmune disease Definition Immune system does not react against each individual’s own (self) antigens. This unresponsiveness to self antigens, also called immunological tolerance Immunological tolerance occurs when an immunocompetent host fails to respond to an immunogenic challenge with a specific antigen Autoimmunity and autoimmune disease There exists mechanism which prevent immune response to self antigens, if these mechanisms fail, the immune system may attack the individual’s own cells and tissues. Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases Tolerance Central Tolerance: Inactivation or destruction of the lymphocytes may occur during early development in the bone marrow or Thymus Peripheral Tolerance: Inactivation or destruction of the mature lymphocytes in the peripheral tissues on encounter with self antigens Central Tolerance (T and B cells) Central tolerance occurs during the early differentiation of B cells in the bone marrow and T cells in the thymus B and T cells that bind with high affinity to self-antigens at early stages of development meet apoptotic death called as negative selection Some self-reactive T cells that encounter self antigens in the thymus develop into regulatory T cells and immature B cells in the bone marrow change their receptors (receptor editing) Positive and negative selection in thymus Medulla of thymus Central T Lymphocyte Tolerance If an immature lymphocyte strongly interacts with a self antigen, displayed as a peptide bound to a self major histocompatibility complex (MHC) molecule, that lymphocyte receives signals that trigger apoptosis, and the cell dies before it can complete its maturation Some immature CD4+ T cells that recognize self antigens in the thymus do not die but develop into regulatory T cells and enter peripheral tissues Peripheral T Lymphocyte Tolerance Location : peripheral lymphoid tissues (Secondary lymphoid organ e.g. spleen, lymph nodes) Cells: mature T lymphocytes Mechanisms: Clonal Anergy (functional inactivation) Clonal Deletion/apoptosis (activation induced cell death) Immune suppression: Regulatory T cells T cell activation Activation of T cell requires 2 signals Signal 1: antigen Signal 2: costimulators that are expressed on antigen presenting cells (APCs)  Anergy Functional inactivation of T lymphocytes: recognition of antigen without adequate levels of the second signal (costimulation) TCR interaction with Ag/MHC Lack of co-stimulatory molecules in APC (B7) reacts with CD28 (lymphocyte) Expression of inhibitory molecules (CTLA 4)  Activation Induced Cell Death Repeated activation of mature T lymphocytes by self antigen leading to cell death Coexpression of death receptors and their ligands i.e. Fas and FasL Production of apoptotic proteins in T cells Regulatory T Cells Regulatory T cells (CD4+/CD25+) Generation and function requires a transcription factor called Foxp3 T reg mediates their function through: » soluble factors (IL-10,TGF) » express CTLA-4 » high level expression of IL-2 receptor Central B cell tolerance Elimination of lymphocytes with high affinity receptors for abundant, widely expressed, self antigens Involve immature B cell in the bone marrow Apoptosis Receptor editing: expression of new antigen receptor Peripheral B cell tolerance Anergy Mature B cells when encounter self antigen in peripheral tissues in absence of specific T helper cells, become unable to respond or die by apoptosis Pathogenesis of autoimmune disease Genetic factors: MHC(HLA) and nonMHC genes MHC (HLA) gene Ankylosing spondylitis associated with HLA-B27 Rheumatoid arthritis associated with HLA-DR4 Non MHC gene X-linked polyendocrinopathy and enteropathy associated with Foxp3 gene Crohn's disease (inflammatory bowel disease) associated with NOD-2 Role of Infections Infection of a tissue may induce a local innate immune response, and this may lead to increased production of costimulators and cytokines by tissue antigen presenting cells (APCs). These activated tissue APCs may be able to stimulate self-reactive T cells that encounter self antigens in the tissue. In other words, infection may “break” T cell anergy and promote the activation of self-reactive lymphocytes Role of Infections Molecular mimicry: Some infectious microbes may produce peptide antigens that are similar to, and cross-react with, self antigens. Immune responses to these microbial peptides may result in an immune attack against self antigens Rheumatic fever, in which antibodies against streptococci cross-react with a myocardial antigen and cause heart disease Role of Infections Infections also may injure tissues and release antigens that normally are sequestered from the immune system. For instance, some sequestered antigens (e.g., in the testis, brain and eye) Release of these antigens (e.g., by trauma or infection) may initiate an auto immune reaction against the tissue Case Scenario: Conclusion Autoimmune diseases Mechanism of tolerance Central and peripheral tolerance Factors responsible for autoimmune disease References Abul K. Abbas, Andrew H. Lichtman, Shiv Pillai; Basic Immunology: Functions and disorders of the Immune system,4th edition, Saunders Elsevier Warren levinson, Review of Medical Microbiology and Immunology, 13th edition, McGraw-Hill Education ISBN 978-0-07-181812-4 Peter J. Delves, Seamus J. Martin, Dennis R. Burton, Ivan M. Roitt. Roitt’s EssentialImmunology, 12th edition, Wiley-Blackwell ISBN 978-1- 4051-9683-3 Thank You