This document provides an overview of immunology and tolerance mechanisms:
1. It begins with a historical perspective on immunology research from Thucydides in 430 BC describing immunity from plague to Edward Jenner's pioneering smallpox vaccination in the late 18th century.
2. The major theories of adaptive immunity are discussed, including clonal selection theory which established the paradigm of lymphocytes recognizing and responding to specific antigens.
3. An overview of the adaptive immune system is given including T cell and B cell functions, antigen presentation by MHC molecules, and the roles of dendritic cells and other antigen presenting cells.
4. Mechanisms of central and peripheral tolerance are summarized which allow the immune system to distinguish
This document provides an overview of transplantation immunology. It discusses the different types of transplants including autografts, allografts, xenografts, and ABO incompatible transplants. It describes how the immune system can reject transplants and the challenges of finding donor-recipient matches. Key concepts covered include acute rejection occurring within 6 months, chronic rejection developing over longer periods, and the use of immunosuppressive drugs to reduce rejection risks. HLA tissue typing aims to find immunologically compatible donors by matching proteins on white blood cells.
Description of various immunological mechanisms involved in the rejection of transplants. Lecture notes for medical, dental and allied health sciences undergraduate medical students.
This document provides an overview of the immune response and immune system. It describes the mechanisms of innate immunity including anatomical, physiological, cellular, and inflammatory barriers that provide non-specific protection. Adaptive immunity is induced when innate immunity fails, and has antigen specificity and immunological memory. B and T lymphocytes mediate humoral and cell-mediated immunity respectively. The process of phagocytosis and antibody production are explained. Primary and secondary immune responses differ in lag period, magnitude, and antibody class. Innate and adaptive immunity cooperate to eliminate pathogens.
The document discusses immunological tolerance and its breakdown which can lead to autoimmunity and autoimmune diseases. It explains the mechanisms of central and peripheral tolerance that normally prevent immune responses against self-antigens. Failure of these tolerance mechanisms can occur through various causes like a breakdown of T cell anergy or loss of regulatory T cells, resulting in an immune response against self-tissues and the development of autoimmune conditions.
This document discusses antigen processing and presentation pathways. It explains that antigens are processed into peptides which are then presented on the surface of antigen presenting cells bound to MHC molecules. There are two pathways: exogenous antigens taken up by cells are processed through the endocytic pathway and presented by MHC class II molecules. Endogenous antigens synthesized within cells use the cytosolic pathway and are presented by MHC class I molecules. Professional antigen presenting cells like dendritic cells, macrophages and B cells present antigens to activate T cells.
T-cells are a type of white blood cell that play a major role in the immune system by fighting infection. There are different types of T-cells that act in various ways to identify and destroy pathogens. T-cells mature in the thymus gland, where they develop receptors called TCRs that allow them to recognize antigens bound to MHC molecules on other cells. The MHC presents antigen fragments to T-cells to trigger an immune response against invading microbes.
This document discusses immunological tolerance and regulatory T cells. It defines tolerance as unresponsiveness to antigen induced by previous exposure. Central tolerance occurs in the thymus through deletion of self-reactive T cells. Peripheral tolerance occurs through several mechanisms in tissues, including regulatory T cells that suppress immune responses. The key transcription factor controlling regulatory T cells is FOXP3. Mutations in FOXP3 can lead to immune dysregulation diseases like IPEX syndrome.
B-cell activation can occur through two routes - dependent or independent of T helper cells. T-helper cells interact with antigen-bound B-cells via CD40/CD40L and B7-CD28 costimulation, releasing cytokines that cause the B-cell to proliferate and differentiate into a plasma cell. The interaction of cytokines and proliferation factors released by T-helper cells provides signals needed for B-cell proliferation and class switching.
T-cell activation requires interaction between the TCR and antigen-bound MHC on an antigen presenting cell, as well as CD28-B7 costimulation, which causes cytokine release and leads to T-cell proliferation, clonal expansion, and differentiation into memory and
This document provides an overview of transplantation immunology. It discusses the different types of transplants including autografts, allografts, xenografts, and ABO incompatible transplants. It describes how the immune system can reject transplants and the challenges of finding donor-recipient matches. Key concepts covered include acute rejection occurring within 6 months, chronic rejection developing over longer periods, and the use of immunosuppressive drugs to reduce rejection risks. HLA tissue typing aims to find immunologically compatible donors by matching proteins on white blood cells.
Description of various immunological mechanisms involved in the rejection of transplants. Lecture notes for medical, dental and allied health sciences undergraduate medical students.
This document provides an overview of the immune response and immune system. It describes the mechanisms of innate immunity including anatomical, physiological, cellular, and inflammatory barriers that provide non-specific protection. Adaptive immunity is induced when innate immunity fails, and has antigen specificity and immunological memory. B and T lymphocytes mediate humoral and cell-mediated immunity respectively. The process of phagocytosis and antibody production are explained. Primary and secondary immune responses differ in lag period, magnitude, and antibody class. Innate and adaptive immunity cooperate to eliminate pathogens.
The document discusses immunological tolerance and its breakdown which can lead to autoimmunity and autoimmune diseases. It explains the mechanisms of central and peripheral tolerance that normally prevent immune responses against self-antigens. Failure of these tolerance mechanisms can occur through various causes like a breakdown of T cell anergy or loss of regulatory T cells, resulting in an immune response against self-tissues and the development of autoimmune conditions.
This document discusses antigen processing and presentation pathways. It explains that antigens are processed into peptides which are then presented on the surface of antigen presenting cells bound to MHC molecules. There are two pathways: exogenous antigens taken up by cells are processed through the endocytic pathway and presented by MHC class II molecules. Endogenous antigens synthesized within cells use the cytosolic pathway and are presented by MHC class I molecules. Professional antigen presenting cells like dendritic cells, macrophages and B cells present antigens to activate T cells.
T-cells are a type of white blood cell that play a major role in the immune system by fighting infection. There are different types of T-cells that act in various ways to identify and destroy pathogens. T-cells mature in the thymus gland, where they develop receptors called TCRs that allow them to recognize antigens bound to MHC molecules on other cells. The MHC presents antigen fragments to T-cells to trigger an immune response against invading microbes.
This document discusses immunological tolerance and regulatory T cells. It defines tolerance as unresponsiveness to antigen induced by previous exposure. Central tolerance occurs in the thymus through deletion of self-reactive T cells. Peripheral tolerance occurs through several mechanisms in tissues, including regulatory T cells that suppress immune responses. The key transcription factor controlling regulatory T cells is FOXP3. Mutations in FOXP3 can lead to immune dysregulation diseases like IPEX syndrome.
B-cell activation can occur through two routes - dependent or independent of T helper cells. T-helper cells interact with antigen-bound B-cells via CD40/CD40L and B7-CD28 costimulation, releasing cytokines that cause the B-cell to proliferate and differentiate into a plasma cell. The interaction of cytokines and proliferation factors released by T-helper cells provides signals needed for B-cell proliferation and class switching.
T-cell activation requires interaction between the TCR and antigen-bound MHC on an antigen presenting cell, as well as CD28-B7 costimulation, which causes cytokine release and leads to T-cell proliferation, clonal expansion, and differentiation into memory and
Lect 2 cells of immune system rmc 2016Hassan Ahmad
The document summarizes key aspects of cells of the immune system:
1. Hematopoietic stem cells in the bone marrow give rise to two main immune cell lineages - the lymphoid lineage which includes T cells, B cells, and NK cells, and the myeloid lineage which includes macrophages, dendritic cells, and granulocytes.
2. T cells develop and mature in the thymus, undergoing positive and negative selection to eliminate self-reactive cells. Mature T cells express either CD4 or CD8 and have a specific T cell receptor.
3. B cells develop and mature in the bone marrow, also undergoing selection to eliminate self-reactive cells.
This document summarizes a presentation on innate immunity. It defines innate immunity and outlines the evolution of the immune system from early pioneers like Jenner and Pasteur. It then describes the components of the innate system including physical and chemical barriers, pattern recognition receptors, phagocytic cells, toll-like receptors, complement system, and inflammation. It also discusses two case scenarios involving innate immunity and provides references for further information.
Cytokines are low molecular weight polypeptides or glycoproteins that are secreted by cells and have various functions including mediating and regulating immune responses and inflammatory reactions. Cytokines are produced by lymphocytes, monocytes, macrophages, mast cells, glial cells and other cells. They act through autocrine, paracrine or endocrine mechanisms and initiate their actions by binding to specific membrane receptors. Cytokines have pleiotropic, redundant, synergistic and antagonistic effects and form a cytokine network. The major classes of cytokines include interleukins, tumor necrosis factors, interferons, colony stimulating factors, transforming growth factors and chemokines. Cytokines play important roles in various diseases and their therapeutic uses include treatment
The document discusses T cells and B cells. It explains that T cells mature in the thymus gland and recognize antigens bound to MHC molecules, while B cells mature in the bone marrow and recognize free antigens. The document then describes the processes of T cell and B cell activation, differentiation, positive and negative selection, and how they contribute differently to the adaptive immune response.
This document discusses cellular immune response and the roles of its key components. It describes how antigen presenting cells present antigens to T lymphocytes via MHC molecules, providing the necessary stimulatory and co-stimulatory signals for T cell activation. Activated T cells then differentiate into effector and memory T cells. Effector CD8+ T cells induce apoptosis of infected cells, while effector CD4+ T cells secrete cytokines to activate macrophages. The interactions between these immune cells are regulated by cytokines. The document also discusses antigen presentation pathways, T cell maturation in the thymus, and the roles of superantigens and cytokines in the immune response.
This document discusses transplantation antigens and mechanisms of transplant rejection. It defines types of transplantation including autografts, allografts, and xenografts. The major histocompatibility complex (MHC) plays an important role in antigen presentation and recognition, with MHC matching reducing rejection. Rejection can occur via antibody-mediated or T cell mediated mechanisms. Immunosuppressive drugs are used to prevent rejection by targeting lymphocytes and immune responses. The fetus is not rejected by the mother due to weak MHC expression on the placenta which acts as a barrier between maternal and fetal tissues.
Natural killer (NK) cells are cytotoxic lymphocytes that play an important role in the innate immune system analogous to cytotoxic T cells in the adaptive immune system. NK cells differentiate and mature in the bone marrow, lymph nodes, spleen, tonsils and thymus before entering circulation. They recognize and kill stressed, virally infected, or tumor cells through either direct cytolytic granule release or antibody-dependent cellular cytotoxicity. Cytokines released during viral infection activate NK cells to secrete interferon gamma and tumor necrosis factor alpha to help control viral spread and recruit other immune cells.
This document provides an introduction to immunology. It defines immunology as the study of the immune system and its functions in health and disease. The immune system recognizes, attacks, and remembers pathogens that enter the body using innate and adaptive defenses. Key events in immunology history are described, such as Edward Jenner's discovery of vaccination and the eradication of smallpox. Components of the immune system like antibodies, lymphocytes, and the complement system are introduced. The document also distinguishes between innate immunity, which provides non-specific defenses, and adaptive immunity, which has memory and specificity.
B-cells develop and mature in the bone marrow from stem cells through distinct stages marked by specific cell surface markers and patterns of immunoglobulin gene expression. Mature B-cells leave the bone marrow and travel to peripheral lymphoid tissues where they are activated upon encountering antigen to produce plasma cells that secrete antibodies and memory B-cells. B-cell activation involves proliferation, somatic hypermutation, selection, and potential class switching in germinal centers to produce high affinity antibodies and long-lasting immunological memory. This allows for a rapid secondary immune response upon re-exposure to the same antigen.
Transplant immunity discusses the history and immunological basis of organ transplantation. It provides an outline of topics including the types of rejection, effector mechanisms, laboratory workup, immunosuppressive therapy, and individual transplant procedures. The document traces the evolution of the field from early mythology to modern transplantation techniques and immunosuppression, highlighting key discoveries like the identification of MHC antigens and development of drugs that enabled successful unrelated donor transplants.
Transplant immunology involves the transplantation of organs or tissues from one individual to another. There are several types of transplants classified based on the organ/tissue and donor-recipient relationship. Major histocompatibility complexes (MHCs) play a key role in triggering immune rejection responses. Graft rejection occurs via sensitization and effector phases, resulting in hyperacute, acute, or chronic rejection. Immunosuppressive drugs are used to prevent rejection, particularly of acute rejection which is most common. Careful matching of donor and recipient MHCs is important to minimize rejection.
Major Compatibility Complex & TransplantationAman Ullah
The major histocompatibility complex (MHC) located on chromosome 6 encodes human leukocyte antigen (HLA) proteins that are important for the success of organ transplants. There are two classes of MHC proteins - class I proteins found on all cells and class II proteins found on antigen presenting cells. Compatibility of the HLA proteins between donor and recipient is important to prevent immune rejection, as mismatched HLA proteins will trigger an immune response. Laboratory tests such as HLA typing by DNA sequencing or serology are used to match donors and recipients as closely as possible based on their MHC genes to improve transplant success.
This document provides information on MHC class I and class II molecules, including their structure, function, and role in antigen presentation. It discusses that MHC class I molecules are expressed on all nucleated cells and present intracellular antigens to CD8+ T cells. MHC class II molecules are expressed primarily on antigen presenting cells and present extracellular antigens to CD4+ T cells. The peptide binding grooves of MHC class I and II molecules differ in their structure and the size of peptides they can bind.
This document discusses tumor immunology and cancer immunotherapy. It provides information on tumor antigens, how tumors stimulate an immune response, and mechanisms tumors use to evade the immune system. The document also outlines several approaches to cancer immunotherapy, including monoclonal antibodies, cytokines, and adoptive cell therapy. A brief history of cancer immunotherapy is given, noting early experiments in the 1890s using bacterial toxins to treat tumors and discoveries in the 1960s about antibody receptors and T cells recognizing cancer cells.
Immunology is the study of the physiological mechanisms that defend the body against pathogens like bacteria, viruses, fungi and parasites. The immune system uses innate and adaptive immunity. Innate immunity acts from the start of an infection non-specifically, while adaptive immunity develops antigen-specific B and T lymphocytes that provide immunological memory. Key cells involved include lymphocytes, monocytes, macrophages, dendritic cells and granulocytes like neutrophils, eosinophils and basophils. Antibodies, cytokines and cellular responses work together to recognize and eliminate invading pathogens.
The document discusses major histocompatibility complexes (MHCs), which are glycoproteins found on cell surfaces that present antigen fragments to T cells. It describes MHC Class I and Class II molecules, which present antigens from intracellular and extracellular pathogens, respectively. MHC genes were first identified as important in tissue graft rejection and show high polymorphism between individuals.
Recognition of transplanted cells is determined by polymorphic MHC genes inherited from both parents. Alloantigen elicit cell-mediated and humoral immune responses from components like antigen presenting cells, B cells, antibodies, and T cells. Cytokines also mediate graft rejection. HLA matching and immunosuppressive drugs are used to minimize rejection, but chronic rejection remains a problem. New methods using genomic analysis and RNA sequencing are being developed to better determine HLA type for transplantation matching.
This document provides an overview of antigen processing and presentation. It discusses that antigen processing is needed to generate peptide fragments from proteins that can bind MHC molecules and be recognized by T cells. It describes the separate pathways for endogenous and exogenous antigen processing, which involve the cytosolic and endocytic pathways, respectively. The key steps in each pathway include protein degradation, peptide transport, and loading onto MHC class I or II molecules. The pathways ensure that intracellular and extracellular antigens are presented through distinct MHC complexes to CD8+ or CD4+ T cells to initiate appropriate immune responses.
Lect 2 cells of immune system rmc 2016Hassan Ahmad
The document summarizes key aspects of cells of the immune system:
1. Hematopoietic stem cells in the bone marrow give rise to two main immune cell lineages - the lymphoid lineage which includes T cells, B cells, and NK cells, and the myeloid lineage which includes macrophages, dendritic cells, and granulocytes.
2. T cells develop and mature in the thymus, undergoing positive and negative selection to eliminate self-reactive cells. Mature T cells express either CD4 or CD8 and have a specific T cell receptor.
3. B cells develop and mature in the bone marrow, also undergoing selection to eliminate self-reactive cells.
This document summarizes a presentation on innate immunity. It defines innate immunity and outlines the evolution of the immune system from early pioneers like Jenner and Pasteur. It then describes the components of the innate system including physical and chemical barriers, pattern recognition receptors, phagocytic cells, toll-like receptors, complement system, and inflammation. It also discusses two case scenarios involving innate immunity and provides references for further information.
Cytokines are low molecular weight polypeptides or glycoproteins that are secreted by cells and have various functions including mediating and regulating immune responses and inflammatory reactions. Cytokines are produced by lymphocytes, monocytes, macrophages, mast cells, glial cells and other cells. They act through autocrine, paracrine or endocrine mechanisms and initiate their actions by binding to specific membrane receptors. Cytokines have pleiotropic, redundant, synergistic and antagonistic effects and form a cytokine network. The major classes of cytokines include interleukins, tumor necrosis factors, interferons, colony stimulating factors, transforming growth factors and chemokines. Cytokines play important roles in various diseases and their therapeutic uses include treatment
The document discusses T cells and B cells. It explains that T cells mature in the thymus gland and recognize antigens bound to MHC molecules, while B cells mature in the bone marrow and recognize free antigens. The document then describes the processes of T cell and B cell activation, differentiation, positive and negative selection, and how they contribute differently to the adaptive immune response.
This document discusses cellular immune response and the roles of its key components. It describes how antigen presenting cells present antigens to T lymphocytes via MHC molecules, providing the necessary stimulatory and co-stimulatory signals for T cell activation. Activated T cells then differentiate into effector and memory T cells. Effector CD8+ T cells induce apoptosis of infected cells, while effector CD4+ T cells secrete cytokines to activate macrophages. The interactions between these immune cells are regulated by cytokines. The document also discusses antigen presentation pathways, T cell maturation in the thymus, and the roles of superantigens and cytokines in the immune response.
This document discusses transplantation antigens and mechanisms of transplant rejection. It defines types of transplantation including autografts, allografts, and xenografts. The major histocompatibility complex (MHC) plays an important role in antigen presentation and recognition, with MHC matching reducing rejection. Rejection can occur via antibody-mediated or T cell mediated mechanisms. Immunosuppressive drugs are used to prevent rejection by targeting lymphocytes and immune responses. The fetus is not rejected by the mother due to weak MHC expression on the placenta which acts as a barrier between maternal and fetal tissues.
Natural killer (NK) cells are cytotoxic lymphocytes that play an important role in the innate immune system analogous to cytotoxic T cells in the adaptive immune system. NK cells differentiate and mature in the bone marrow, lymph nodes, spleen, tonsils and thymus before entering circulation. They recognize and kill stressed, virally infected, or tumor cells through either direct cytolytic granule release or antibody-dependent cellular cytotoxicity. Cytokines released during viral infection activate NK cells to secrete interferon gamma and tumor necrosis factor alpha to help control viral spread and recruit other immune cells.
This document provides an introduction to immunology. It defines immunology as the study of the immune system and its functions in health and disease. The immune system recognizes, attacks, and remembers pathogens that enter the body using innate and adaptive defenses. Key events in immunology history are described, such as Edward Jenner's discovery of vaccination and the eradication of smallpox. Components of the immune system like antibodies, lymphocytes, and the complement system are introduced. The document also distinguishes between innate immunity, which provides non-specific defenses, and adaptive immunity, which has memory and specificity.
B-cells develop and mature in the bone marrow from stem cells through distinct stages marked by specific cell surface markers and patterns of immunoglobulin gene expression. Mature B-cells leave the bone marrow and travel to peripheral lymphoid tissues where they are activated upon encountering antigen to produce plasma cells that secrete antibodies and memory B-cells. B-cell activation involves proliferation, somatic hypermutation, selection, and potential class switching in germinal centers to produce high affinity antibodies and long-lasting immunological memory. This allows for a rapid secondary immune response upon re-exposure to the same antigen.
Transplant immunity discusses the history and immunological basis of organ transplantation. It provides an outline of topics including the types of rejection, effector mechanisms, laboratory workup, immunosuppressive therapy, and individual transplant procedures. The document traces the evolution of the field from early mythology to modern transplantation techniques and immunosuppression, highlighting key discoveries like the identification of MHC antigens and development of drugs that enabled successful unrelated donor transplants.
Transplant immunology involves the transplantation of organs or tissues from one individual to another. There are several types of transplants classified based on the organ/tissue and donor-recipient relationship. Major histocompatibility complexes (MHCs) play a key role in triggering immune rejection responses. Graft rejection occurs via sensitization and effector phases, resulting in hyperacute, acute, or chronic rejection. Immunosuppressive drugs are used to prevent rejection, particularly of acute rejection which is most common. Careful matching of donor and recipient MHCs is important to minimize rejection.
Major Compatibility Complex & TransplantationAman Ullah
The major histocompatibility complex (MHC) located on chromosome 6 encodes human leukocyte antigen (HLA) proteins that are important for the success of organ transplants. There are two classes of MHC proteins - class I proteins found on all cells and class II proteins found on antigen presenting cells. Compatibility of the HLA proteins between donor and recipient is important to prevent immune rejection, as mismatched HLA proteins will trigger an immune response. Laboratory tests such as HLA typing by DNA sequencing or serology are used to match donors and recipients as closely as possible based on their MHC genes to improve transplant success.
This document provides information on MHC class I and class II molecules, including their structure, function, and role in antigen presentation. It discusses that MHC class I molecules are expressed on all nucleated cells and present intracellular antigens to CD8+ T cells. MHC class II molecules are expressed primarily on antigen presenting cells and present extracellular antigens to CD4+ T cells. The peptide binding grooves of MHC class I and II molecules differ in their structure and the size of peptides they can bind.
This document discusses tumor immunology and cancer immunotherapy. It provides information on tumor antigens, how tumors stimulate an immune response, and mechanisms tumors use to evade the immune system. The document also outlines several approaches to cancer immunotherapy, including monoclonal antibodies, cytokines, and adoptive cell therapy. A brief history of cancer immunotherapy is given, noting early experiments in the 1890s using bacterial toxins to treat tumors and discoveries in the 1960s about antibody receptors and T cells recognizing cancer cells.
Immunology is the study of the physiological mechanisms that defend the body against pathogens like bacteria, viruses, fungi and parasites. The immune system uses innate and adaptive immunity. Innate immunity acts from the start of an infection non-specifically, while adaptive immunity develops antigen-specific B and T lymphocytes that provide immunological memory. Key cells involved include lymphocytes, monocytes, macrophages, dendritic cells and granulocytes like neutrophils, eosinophils and basophils. Antibodies, cytokines and cellular responses work together to recognize and eliminate invading pathogens.
The document discusses major histocompatibility complexes (MHCs), which are glycoproteins found on cell surfaces that present antigen fragments to T cells. It describes MHC Class I and Class II molecules, which present antigens from intracellular and extracellular pathogens, respectively. MHC genes were first identified as important in tissue graft rejection and show high polymorphism between individuals.
Recognition of transplanted cells is determined by polymorphic MHC genes inherited from both parents. Alloantigen elicit cell-mediated and humoral immune responses from components like antigen presenting cells, B cells, antibodies, and T cells. Cytokines also mediate graft rejection. HLA matching and immunosuppressive drugs are used to minimize rejection, but chronic rejection remains a problem. New methods using genomic analysis and RNA sequencing are being developed to better determine HLA type for transplantation matching.
This document provides an overview of antigen processing and presentation. It discusses that antigen processing is needed to generate peptide fragments from proteins that can bind MHC molecules and be recognized by T cells. It describes the separate pathways for endogenous and exogenous antigen processing, which involve the cytosolic and endocytic pathways, respectively. The key steps in each pathway include protein degradation, peptide transport, and loading onto MHC class I or II molecules. The pathways ensure that intracellular and extracellular antigens are presented through distinct MHC complexes to CD8+ or CD4+ T cells to initiate appropriate immune responses.
This document summarizes T lymphocyte development and activation. It describes how progenitor cells commit to the T cell lineage in the bone marrow and thymus. In the thymus, T cells undergo proliferation, rearrangement of T cell receptor genes, and positive and negative selection. This results in functionally distinct T cell subsets that migrate to lymph nodes upon activation. T cell activation requires three signals - engagement of the T cell receptor by peptide-MHC complexes, costimulatory molecules such as CD28 binding to B7, and cytokine signals. This leads to intracellular signaling cascades and expression of genes regulating T cell effector function.
Antigen presenting cells such as dendritic cells, macrophages, and B cells capture antigens through mechanisms like phagocytosis and present antigen peptides bound to MHC molecules to T cells. This activation of T cells is required for the adaptive immune response against pathogens. Dendritic cells are especially efficient at antigen presentation and activation of naive T cells. Antigens that enter cells through endocytosis are processed through the MHC class II pathway and presented to CD4+ T cells, while intracellular antigens use the MHC class I pathway to activate CD8+ T cells. Antigen presenting cells play an important role in periodontal diseases by regulating the immune response and migration between infected tissues and lymph nodes.
ANTIGEN PROCESSING PRESENTATION AND RECOGNITION - Copy [Autosaved].pptxSamboZailani1
This is a medical students' lecture.
It is among the immunology lectures. it is important for a medical student to understand immunology to some extent.
Studying the Adaptive Immune Response - Tools for T & B Cell Research: Host D...QIAGEN
Adaptive immunity, powered by T cells and B cells, provides specific, long-lasting protection of the host from harmful invaders. This slidedeck provides an overview of T cells and B cells and their role in cell-mediated immune responses and antibody responses, respectively, against pathogens. There is also information on tools that enable analysis of T and B cell gene expression and regulation, genotyping and signal transduction pathway activation.
dkNET-HIRN Webinar "T Cell Antigen Discovery: Experimental and Computational ...dkNET
dkNET New Investigator Pilot Program in Bioinformatics Awardee Seminar Series
Co-Hosted with Human Islet Research Network (HIRN)
Presenter: Alok V. Joglekar, Ph.D. Assistant Professor, Center for Systems Immunology and Department of Immunology, University of Pittsburgh School of Medicine
Abstract
T cells are key players in many autoimmune diseases including Type 1 Diabetes. T cell responses are highly antigen specific by virtue of their T cell receptors (TCRs), that recognize epitopes on target cells. The enormous diversity of TCRs in an immune response poses a challenge in studying them, particularly regarding their antigenic specificity. Several experimental approaches have been developed to identify T cell specificities, with a recent surge in cell-based assays. More recently, computational approaches to predict T cell specificity are being developed and show great promise. This webinar will provide an overview of the experimental and computational approaches to identify T cell antigens. Furthermore, we will highlight the research performed in the Joglekar lab towards applying these approaches for auto-antigen discovery in Type 1 Diabetes. Finally, we will project what the future of these approaches may be, particularly for studying autoimmune diseases.
This document provides information about Dr. Samia Hawas, a professor of medical microbiology and immunology. It then provides a high-level overview of innate and adaptive immunity, including their components and functions. Finally, it discusses key immune cells and concepts in more detail, such as lymphocytes, antigens, phagocytosis, and antigen presentation.
[DOCUMENT]:
This document provides an overview of immunogenetics. It begins with an agenda that defines immunogenetics and discusses immune responses, diversity mechanisms, and immunodeficiency diseases. The document then defines immunogenetics as the study of genetic control of immune cells and molecules. It focuses on structure and organization of immune response genes, HLA antigens and disease association, generation of antibody and T cell diversity. Mechanisms creating diversity for B cell receptors, T cell receptors and HLA are described. Finally, immunodeficiency diseases associated with impaired immune function are briefly discussed.
Dendritic cell vaccines show potential for treating high grade glial tumors. Dendritic cells can present tumor antigens to activate CD8 and CD4 T cells. They undergo a maturation process where they migrate to lymph nodes, interact with T cells and release cytokines to stimulate an immune response. Dendritic cells can be obtained from patients and loaded with tumor antigens ex vivo before being reinfused to induce anti-tumor immunity. Multiple methods are being studied to enhance dendritic cell vaccines including combination with other immunotherapies.
1. T cells develop from progenitor cells in the thymus and bone marrow through a process involving commitment to the T cell lineage, proliferation, rearrangement of T cell receptor genes, selection processes, and differentiation into mature subsets.
2. Key stages of T cell maturation include double negative, double positive, and single positive stages, driven by signals from the pre-T cell receptor and selection in the thymus.
3. T cell receptor diversity is generated through rearrangement of variable, diversity, and joining gene segments and addition of nucleotides at junctions.
This research article demonstrates the use of Wavelength Modulated Raman Spectroscopy (WMRS) to identify major immune cell subsets in an unlabeled and non-fixed state. Using WMRS, the researchers were able to distinguish between CD4+ T lymphocytes, CD8+ T lymphocytes, and CD56+ Natural Killer cells from multiple donors with up to 96% specificity. They also distinguished between CD303+ plasmacytoid and CD1c+ myeloid dendritic cell subsets. This label-free method opens new opportunities for analyzing immune systems and developing diagnostic technologies without altering or damaging the cells.
1) WASp-deficient dendritic cells (DCs) show impaired activation of naive CD8+ T cells, especially at low antigen doses.
2) This is partly due to altered trafficking of antigen-bearing DCs from the periphery to lymph nodes. However, correcting DC migration does not fully rescue T cell activation.
3) In vitro and in vivo imaging revealed that cytoskeletal alterations in WASp-null DCs reduce their ability to form and maintain conjugates with naive CD8+ T cells in lymph nodes, contributing to defective T cell priming.
This document provides an overview of the immune system. It begins with definitions of immunity and the historical views of disease. It then describes the innate and adaptive immune systems in detail. The innate system includes physical barriers and the complement system. Adaptive immunity involves both humoral immunity through B cells and antibodies, and cell-mediated immunity through T cell subsets. Key immune cells like macrophages and neutrophils are also summarized in terms of their functions, including phagocytosis, antigen presentation, and cytokine secretion. The document provides an extensive but concise review of immune system components and their roles in protection from pathogens.
1) Antigen presenting cells (APCs) such as dendritic cells, macrophages, and B cells present antigen peptides on their surfaces to activate T cells.
2) APCs capture antigens through phagocytosis, pinocytosis, or receptor-mediated endocytosis and process the antigens into peptides.
3) The peptides are then presented on either MHC class I or MHC class II molecules for recognition by CD8+ or CD4+ T cells respectively, initiating an adaptive immune response.
This document summarizes a study that screened an antibody library to identify antibodies that could induce protective immune responses by targeting dendritic cells. The screening identified an antibody against CD36, a receptor expressed on CD8α+ dendritic cells. The antibody was linked to the model antigen OVA and shown to deliver the antigen for both MHC class I and II processing in vitro and in vivo. Immunization with the anti-CD36-OVA antibody induced robust activation of naive CD4+ and CD8+ T cells and differentiation of primed CD8+ T cells into long-term effector cytotoxic T lymphocytes. Vaccination protected against tumor growth in a tumor-specific antigen model. Targeting CD36 was qualitatively different than targeting DEC
1) The document discusses tumor immunology and mechanisms of tumor immune evasion. It describes how tumors can downregulate MHC expression, secrete immunosuppressive factors, inhibit T cell function through checkpoint pathways like PD-1/PD-L1, and recruit immunosuppressive cells like Tregs.
2) Checkpoint pathways like CTLA-4 and PD-1 normally regulate T cell activation, but tumors can exploit these pathways to evade immune destruction by overexpressing ligands that bind these inhibitory receptors.
3) Several immunotherapies targeting CTLA-4 and PD-1/PD-L1 have been developed including ipilimumab, nivolumab, pembrol
JC Virus of the CNS classically presents as progressive multifocal leukoencephalopathy, but on rare occasion can manifest as septic meningitis. Slides compares the presentation, workup and treatment in both forms.
CAR T cells show promise for treating rheumatologic diseases. They involve genetically modifying a patient's T cells to express a chimeric antigen receptor (CAR) that targets specific proteins on autoreactive B cells. First-generation CAR T cells contain an antibody-derived antigen binding domain, while later generations add costimulatory domains for improved activation and persistence. CAR T cells have depleted B cells and reduced autoantibodies in mouse models of lupus and human case studies of severe refractory SLE. They have also shown effectiveness against antisynthetase syndrome by reversing manifestations after other treatments failed. Further studies are still needed regarding their long-term safety, durability of remission, and cost effectiveness before they can be widely
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How to Manage Your Lost Opportunities in Odoo 17 CRMCeline George
Odoo 17 CRM allows us to track why we lose sales opportunities with "Lost Reasons." This helps analyze our sales process and identify areas for improvement. Here's how to configure lost reasons in Odoo 17 CRM
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
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Chapter wise All Notes of First year Basic Civil Engineering.pptxDenish Jangid
Chapter wise All Notes of First year Basic Civil Engineering
Syllabus
Chapter-1
Introduction to objective, scope and outcome the subject
Chapter 2
Introduction: Scope and Specialization of Civil Engineering, Role of civil Engineer in Society, Impact of infrastructural development on economy of country.
Chapter 3
Surveying: Object Principles & Types of Surveying; Site Plans, Plans & Maps; Scales & Unit of different Measurements.
Linear Measurements: Instruments used. Linear Measurement by Tape, Ranging out Survey Lines and overcoming Obstructions; Measurements on sloping ground; Tape corrections, conventional symbols. Angular Measurements: Instruments used; Introduction to Compass Surveying, Bearings and Longitude & Latitude of a Line, Introduction to total station.
Levelling: Instrument used Object of levelling, Methods of levelling in brief, and Contour maps.
Chapter 4
Buildings: Selection of site for Buildings, Layout of Building Plan, Types of buildings, Plinth area, carpet area, floor space index, Introduction to building byelaws, concept of sun light & ventilation. Components of Buildings & their functions, Basic concept of R.C.C., Introduction to types of foundation
Chapter 5
Transportation: Introduction to Transportation Engineering; Traffic and Road Safety: Types and Characteristics of Various Modes of Transportation; Various Road Traffic Signs, Causes of Accidents and Road Safety Measures.
Chapter 6
Environmental Engineering: Environmental Pollution, Environmental Acts and Regulations, Functional Concepts of Ecology, Basics of Species, Biodiversity, Ecosystem, Hydrological Cycle; Chemical Cycles: Carbon, Nitrogen & Phosphorus; Energy Flow in Ecosystems.
Water Pollution: Water Quality standards, Introduction to Treatment & Disposal of Waste Water. Reuse and Saving of Water, Rain Water Harvesting. Solid Waste Management: Classification of Solid Waste, Collection, Transportation and Disposal of Solid. Recycling of Solid Waste: Energy Recovery, Sanitary Landfill, On-Site Sanitation. Air & Noise Pollution: Primary and Secondary air pollutants, Harmful effects of Air Pollution, Control of Air Pollution. . Noise Pollution Harmful Effects of noise pollution, control of noise pollution, Global warming & Climate Change, Ozone depletion, Greenhouse effect
Text Books:
1. Palancharmy, Basic Civil Engineering, McGraw Hill publishers.
2. Satheesh Gopi, Basic Civil Engineering, Pearson Publishers.
3. Ketki Rangwala Dalal, Essentials of Civil Engineering, Charotar Publishing House.
4. BCP, Surveying volume 1
How to Fix the Import Error in the Odoo 17Celine George
An import error occurs when a program fails to import a module or library, disrupting its execution. In languages like Python, this issue arises when the specified module cannot be found or accessed, hindering the program's functionality. Resolving import errors is crucial for maintaining smooth software operation and uninterrupted development processes.
A review of the growth of the Israel Genealogy Research Association Database Collection for the last 12 months. Our collection is now passed the 3 million mark and still growing. See which archives have contributed the most. See the different types of records we have, and which years have had records added. You can also see what we have for the future.
1. DEPARTMENT OF
PHYSIOLOGY
Saturday, December 5, 2020 1
Presenter:
Dr. Aishee Pal
Junior Resident (Acad)
Moderator:
Dr. Nasreen Akhtar
How we avoid attack on
our own cells and
tissues?
2. Overview
• Introduction
• Overview of Adaptive Immune System
• Major Histocompatibility Complex
• T and B cells: Types, Receptor, Structure, Activation
• Immunological Synapse
• Antigen Presenting Cells (APCs) and Dendritic Cells (DCs)
• Immunotolerance : Overview
• Central and Peripheral Tolerance: Mechanisms
• Applied Aspects
• Summary
Saturday, December 5, 2020 2
3. A Historical Perspective of Immunology
Saturday, 05 December 2020 3
In
, the great historian of the PeloponnesianWar
college.columbia.edu
TIMELINE SCIENTIST RESEARCH FIELD
430 BC Thucydides • Described a plague in Athens
• Those who had recovered from the plague could nurse the sick
because they would not contract the disease a second time.
In 15th
Century
Chinese and Turks
1718 Lady Mary Wortley
Montagu
• Observed POSITIVE effects of variolation on the native Turkish
population and had performed the technique on her own
children.
1798 Edward Jenner
Father of Immunology
• Observed milkmaids not contracting smallpox infection apparently as
they were exposed to a similar form of disease-cowpox.
• He inoculated Master Phillips with fluid from cowpox pustule
later infected intestinally with small pox NO SMALL POX
4. Saturday, 05 December 2020 6
1890: Emil von Behring and Shibasaburo Kitasato
• Nobel Prize in Physiology or Medicine in 1901 for giving first insights into the mechanism of
immunity)
• Tetanus antitoxin
5. 1930: Elvin Kabat
Saturday, 05 December 2020 7
Because immunity is mediated by antibodies
contained in body fluids (known at that time as humors),
called as humoral immunity
Merrill Chase
• 1940: Transferred immunity against - WBC from immune guinea pigs
• 1950s - lymphocyte - cellular and humoral immunity
Bruce Glick
• Using chickens - two types of lymphocytes
• T lymphocytes - thymus - cellular immunity
• B lymphocytes - bursa of Fabricius - humoral immunity
6. Early theories to explain specificity of Antigen-Antibody interaction
Saturday, 05 December 2020 8
Selective theory Instructional theory
• Given by Paul Ehrlich in
1900
• Cells in blood expressed
receptors:“side-chain
receptors”
• React and bind with infectious
agents: “lock and key
mechanism”
• Induce cell to produce and
release more similar
receptors
• Specificity of Receptor-
Predetermined
• Antigen select the appropriate
Receptor
• Given by Friedrich Breinl and Felix
Haurowitz
(1930s and 1940s)
• A particular antigen - template
• Antibody would fold around template - assume
complementary configuration
Redefined by Niels Jerne, David
Talmadge, F. Macfarlane Burnet:
The clonal selection
theory
7. Saturday, 05 December 2020 9
The clonal selection theory-underlying
paradigm of modern immunology
Antigen interacting with a receptor on a
lymphocyte
Division and Differentiation of that
lymphocyte
Formation of
clone of
identical
daughter cells
bearing the same
receptor as the
stimulated cell
Immature stage of cloned B cells meeting
antigen during development are eliminated
Antibodies produced by
B cells stimulated by
clonal selection will share
the
antigen-binding site with
the membrane receptor of
the stimulated cell
Representatives of the stimulated clones remain
in the host as “immunological memory”
Antigen Elimination
Kuby et al, Immunology, 7th ED
8. Saturday, 05 December 2020 10
Macfarlane Burnet
1. HSC
2. Immature lymphocytes with Ag receptors
3. Those that bind to self Ag - destroyed
4. Rest mature to inactive lymphocytes
5. Encounter foreign antigen- activated
6. Produce many clones of themselves
The Clonal Selection Theory
Hypothesis
9. DEFINITIONS
• Immunoreactivity:
Immune reaction caused by an antigen
• Immunotolerance:
It is the phenomenon of indifference or non-reactivity or unresponsiveness towards a
substance/antigen that would normally be expected to elicit an immunological response
induced by exposure of lymphocytes to that antigen.
Saturday, December 5, 2020 11
Kuby, Immunology, 8th Ed, 2019
Robbins, Pathologic Basis of Disease, 10th Ed, 2020
10. Overview of Adaptive Immune System
Saturday, December 5, 2020
12
T cell TCR Ag
B cell
BCR
11. Types of Receptor Binding
The ratio of the time spent in the “on” versus the “off” state determines:
• AFFINITY of the receptor-ligand interaction
• AVIDITY - the strength of the noncovalent binding between receptor and ligand
Antigen recognition by T cells is qualitatively different from that of B cells
Saturday, December 5, 2020 13
MONOVALENT
BINDING
T cell Receptor
BIVALENT BINDING
B Cell Receptor
Kuby, Immunology, 8th Ed, 2019
12. T cells: Types, Functions and Secretions
Th1 • Promotes production of opsonizing antibodies (IgG),
cytotoxic T cell development and delayed-type
hypersensitivity (DTH)
• Transcription Factor: T-Bet positive
IFN-gamma
IL-2
Th2 • Stimulate eosinophil development via IL-5
• Mediate immunity against parasitic infestations AND Chronic
eosinophilic inflammation via IgE
• Transcription Factor: GATA-3 positive
IL-4, IL-5, IL-13, and IL-10
Th9 • Antitumor immunity, allergy, and autoimmune disease IL-9 and IL-10
Follicular
Helper T
cell
• Recruits neutrophils: early involvement against extracellular
pathogens
• Chronic inflammatory responses in chronic infection, allergy,
autoimmunity
IL-17A: induces production of
proinflammatory cytokines &
chemokines
Treg cell • Establishment and maintenance of peripheral tolerance
suppressing (Negative Selection Process) the immune
response
• Transcription Factor: FOX-P3 positive
IL-12, IL-23, CD-4/45/
FOX-P3, TGF-beta
Cytotoxic
T cell
• Kills infected cells by damaging the target cells or inhibiting
microbial replication
T cell/target cell adhesion
molecule interactions
(eg: CD2 with CD58,
CD11a/CD18 with CD54CD54Saturday, December 5, 2020 14
CD4/
MHC II
CD8/
MHC I
Kuby, Immunology, 8th Ed, 2019
13. Function of B and T cells
Saturday, December 5, 2020 15
Robbins, Pathologic Basis of Disease, 10th Ed
14. Major Histocompatibilty Complex
• Tightly linked cluster of genes in chromosome 6p
16Saturday, 05 December 2020
GENES Associated:
• Class I: (HLA A, B, C)
• Class II:(HLA DQ, DR,
DP)
• Class III :Complement
system: C4, C2, and Bf
• Class IV : Tumor
Necrosis Factor (TNF)-
α and β, genes like
B144, AIF1, and the
MIC family.
MHC Class I MHC Class II
Source of Antigen Intracellular Extracellular
pathogens
Antigen Binding Groove Closed Open
Degraded in Cytosol Endocytic vesicles
Expression All nucleated cells Professional APCs
Antigen Presented to CD8 T cells CD4 T cells
Effect Cell death Pathogen is killed
15. T Cell Receptor : Structure
Saturday, December 5, 2020 17
• (TCR) alpha-beta (TCR2) or gamma-delta (TCR1) heterodimer.
• αβ TCR: recognizes peptide antigens that are presented by MHC
molecules on the surfaces of APCs.
• γδ TCR: recognizes peptides, lipids, and small molecules, without
presentation to MHC proteins.
• The α and β chains of TCR lack cytoplasmic extensions, thus
communicate with the interior of the cell through a single-span
transmembrane, CD3 family
• TCR-CD3 Complex: Initiates signal transduction by
Phosphorylation of ITAM motifs and regulation of catalytic activity
via protein tyrosine kinases: Lck and ZAP-70Chromosomal location of TCR chains
Alpha, Delta 14q11
Beta 7q35
Gamma 7p15
Immuno-receptor Tyrosine Activation Motif
16. T cell Receptor Activation: The three-signal model of T cell
activation
Saturday, December 5, 2020
18
Antigen binds weakly to TCR
SIGNAL 1: ALLORECOGNITION
TCR-CD3-Peptide-MHC complex activated by
phosphorylation of ITAMs and Lck protein on
APC
CD4/CD8 coreceptors on T cells
binds to MHC class II/I on APCs
SIGNAL 2: COSTIMULATION
CD28 co-receptor provides another signal
upon binding to costimulatory molecules
CD80 (B7-1)/CD86 (B7-2)
Sayegh et al, N Engl J Med 1998; 338:1813-1821
Kuby et al, Immunology, 8th Ed
SIGNAL 3: CYTOKINE
SIGNALING
Autocrine and Paracrine
Stimulation
17. Saturday, December 5, 2020 19
Leiden JM et al, Annual Rev Immunol 1993; 11:539
Organization of human TCR Gene locus: V(D)J
recombination
TCR chain is encoded by multiple rearranging gene segments:
Alpha locus: Three gene clusters:
49 V; 61 J; 1 C
Beta locus: Four gene clusters:
75 V; 2 D; 2 C; 6 Jβ1; 7 Jβ2
V (variable); J (joining) ; C (constant); D (Diversity)
• TCR genes undergo recombination of the V,D,J genes
called V(D)J recombination.
• This event is dependent upon the function of recombinase-
activating genes 1 and 2 (RAG1 and RAG2)
18. Saturday, December 5, 2020 21
AP
C
T-
Cell
MHCICAM-1/3
or CD54
LFA-1
TCR
CD4/8
B7-1/B7-2
or CD80/86
CD28
Processed antigen
ICAM : Intercellular adhesion molecule
LFA : Lymphocyte function associated antigen 1
Immunological synapse/Steps of antigen presentation
Adhesion
20. Dendritic cells
• Dendritic cells (DCs) : "professional" APCs
• Most Important APC: located at the
MOST COMMON SITE to capture
antigens
• Development of immature DCs: Pattern
recognition receptors, such as "Toll-like"
receptors (TLRs), lectins
• APCs constitutively express high level of
MHC molecules class I/ II molecules
• Types: 1. Plasmacytoid
2. Conventional
3. Follicular
Saturday, December 5, 2020 24
Patente TA at al, 2019, Front. Immunol. 9:3176
22. Functions of Dendritic cells
Saturday, December 5, 2020 26
antigens are presented to T-cells
without the activating co-stimulatory
signals
Development
into Treg cells
AnergyT cell
apoptosis
2. Immature DC : An essential role In the
induction and maintenance of immuno tolerance:
“Tolerogenic DC” express:
1.LESS co-stimulatory
molecules &
proinflammatory cytokines
2. UPREGULATE the
expression of inhibitory
molecules (PD-1 & CTLA-
4)
3. SECRETE
anti-inflammatory
cytokines (IL-10)
1. Critical for the initiation of the immune response: Processing and presenting antigen to T cells by several
means like:
a. engulfment by phagocytosis,
b. internalization by receptor-mediated endocytosis, or
c. imbibition by pinocytosis
Patente TA at al, 2019, Front. Immunol. 9:3176
23. Types of Dendritic cells
Plasmacytoid
DCs
Conventional DCs Follicular DCs
anti-tumor and anti-
virus immunity
• Potent inducers of regulatory T cells in
intestine
• Maintaining tolerance in the liver
• Produce retinoic acid upon stimulation with
vitamin D3,
Stimulating CD4+ naïve T cells to express
gut-homing molecules and Th2 cytokines
• Fc receptors for IgG
and C3b receptors
• Presenting antigens to
B cells in the germinal
center
• They play a role in
humoral immune
responses
Kuby et al, Immunology, 8th Ed,2019
Patente TA at al, 2019, Front. Immunol. 9:3176
24. B Cell Receptor: Structure
Saturday, December 5, 2020 28
Constituents:
• A heterodimer : 2 invariant
proteins, Igα (CD79a) and Igβ
(CD79b)
• CD40: Receives signals from Th
cells.
• Complement receptor: CR2/
CD21
• Signal
transduction
in response
to antigen
recognition,
• Generate
innate
immunity.
• CR2 is also used by EBV as a receptor to enter, infect B
cells.
• Development of B cell memory
Abbas et al, Cellular and Molecular Immunology, 9th Ed, 2017
25. B Cell Receptor: Activation
IgM/IgD: Transmit
signals
Phosphorylation of tyrosine residues in ITAMs motifs
Facilitated by LYN-Src kinase protein
CD21, co-receptor
associated with CD19,
binds to the complement
molecule: C3d
Antigen binds weakly to
BCR
Immuno-receptor Tyrosine Activation Motif ; TAPA-1 (Target of the Antiproliferative
Antibody 1)
Facilitates signal transduction CD19 along with
CD81/TAPA-1
Annu Rev Immunol. 2014;32:283-321
Saturday, October 31, 2020
26. IMMUNOLOGICAL TOLERANCE
Saturday, December 5, 2020 30
• Self-tolerance refers to lack of
responsiveness to an individual’s
own antigens, and it underlies our
ability to live in harmony with our
cells and tissues
Protection from
infections
Prevention of
excess activation
Immunity
Lymphocytes
APC
Central and
Peripheral
tolerance
Robbins, Pathologic Basis of Disease, 10th Ed, 2020
27. FACTORS DETERMINIG IMMUNOGENICITY AND TOLEROGENICITY OF
ANTIGEN
Factors Stimulation of Immune
Response
Induces Tolerance
Time of exposure Short lived (Eliminated by Immune
Response)
Prolonged exposure
Route of exposure Subcutaneous, Intradermal Intravenous, mucosal
Structural
characteristics of
allergen and antigen
Antigens with ADJUVANTS;
Stimulates Th cells
Antigens without ADJUVANTS;
Non-Immunogenic/Tolerogenic
Co-exposure with
stimulators
Low Level of costimulators High Level of costimulators
Saturday, December 5, 2020 31Kuby et al, Immunology, 8th Ed, 2019
28. Overview of Tolerance
Saturday, December 5, 2020 32Male D, Textbook of immunology , 8th ED
Types Central Tolerance Peripheral
Tolerance
Site Primary or Central lymphoid organs
eg THYMUS or BONE MARROW
Peripheral refers to the
secondary or peripheral
lymphoid organs
Cells Involved During development of T and B
lymphocytes
Induced in mature
lymphocytes
Process Involves Immature self-reactive T and B
lymphocyte clones recognizing self
antigens are killed/rendered
harmless
Prevent auto-reactive
mature lymphocytes from
attacking self antigen
29. Saturday, December 5, 2020 33
IMMUNOLOGICAL TOLERANCE
CENTRAL TOLERANCE
PERIPHERAL TOLERANCE
T cells
1. Receptor Editing
by V(D)J
Recombination
2. Negative
selection or
clonal deletion
B cells
1. Negative
selection or
clonal
deletion
2. Clonal Arrest
3. Clonal Anergy
4. Clonal editing
5. Development
of Treg cells.
B cells
1. Anergy
2. Suppressio
n by Treg
cells
3. Deletion by
Apoptosis
1. Anergy:
2. B cell
Intrinsic
Mechanisms
T cells
30. Saturday, December 5, 2020 34
Central T Cell Tolerance
Kuby, Immunology, 8th Ed, 2019; Robbins, Pathologic Basis of Disease, 10th Ed, 2020
31. Saturday, December 5, 2020 35
Central tolerance in Thymus
Role of Positive & Negative selection
Male D, Textbook of immunology , 8th ED
Negative Selection of
cTEC
32. Saturday, December 5, 2020
36
Role of AIRE (AUTOIMMUNE RESPONSE ELEMENT) in
mTECs
mTECs: Medullary Thymic Epithelial Cells
Kuby, Immunology, 8th Ed, 2019;
33. Saturday, December 5, 2020 37
AIRE (AUTOIMMUNE RESPONSE
ELEMENT)
• AIRE encoded on: Chrom 21; region 22q.3, Autosomal Recessive
• Location: Medullary Cortical Thymic Epithelial Cells (mTECs)
• Component of multiple protein complex that
binds to chromatin and regulate the process
of gene transcription
• AIRE comprises (From the N-terminus
moving to the C-terminus ):-
1. CARD : Caspase-Activation and
Recruitment Domain
2. NLS : Nuclear Localization Signal
3. SAND
4. PHD1 and PHD2: 2 zinc fingers Plant-
Homeodomains.
5. PRR : proline-rich region
Schematic representation of human autoimmune regulator
(AIRE).
Perniola R (2018) Twenty Years of AIRE. Front. Immunol. 9:98.
34. Saturday, December 5, 2020 38
.
Functions of AIRE
• Acts as transcriptional regulator, promoting expression of selected tissue-restricted antigen in thymus by
Translation and Chromatin Packing
• Embodies the essence of thymic self-representation
• Promiscus Gene Expression:
Allows mTECs to express proteins not ordinarily found in the thymus
present them using MHC molecules Promotes Self Tolerance
• Formation of scaffold-like meshwork of the intermediate filaments or microtubules
• CARD domain: Homomerization into oligomers, binding to specific oligonucleotide motifs.
• SAND region: Anchorage to heterologous proteins (DNA phosphate group binding)
• CARD, NLS, and SAND domain: Lysine residues, sites of acetylation, key for protein localization
• PHD fingers: 4 cysteine, 1 histidine, 3 Cysteine residue motifs, coordinates two zinc ions.
“Read” the chromatin marks, Degree of methylation at the tail of histone H3.
Perniola R (2018) Twenty Years of AIRE. Front. Immunol. 9:98.
35. Saturday, December 5, 2020 39
Role of Dwell time in T cell selection
Alpha CPM : α-chain
connecting peptide motif
LCK : lymphocyte-specific
protein tyrosine kinase
ITAM : Immune-receptor-
Tyrosine-based-Activation-
Motif
Palmer et al, Nature Reviews Immunology 2009; 207-213
36. Mechanism of Central B cell Tolerance: Receptor editing
A process whereby ongoing antibody gene recombination promotes a change in the
specificity or expression of the antigen receptor of a B cell..
V CD JVV V
BB
Receptor
recognises
self antigen
B Apoptosis
or anergy
BB
Edited receptor now recognises
a different antigen and can be
rechecked for specificity
CD JVV VV
Arrest development of immature B cells:
And reactivate Recombinase Activated Genes:
RAG-1 and RAG-2
Saturday, December 5, 2020 40Nat Rev Immunol. 2017 May ; 17(5): 281–294
37. Saturday, December 5, 2020 41
1. Allelic exclusion promoting Genetic diversity
2. Assembles genes that encode potentially autoreactive antibodies
Central tolerance as a barrier to immunity
• Hinder immune reactions to foreign antigens to which reactivity might be desirable, such as vaccines.
Against HIV
• Neutralizing HIV antigen by IMMUNOTOLERANCE
Nat Rev Immunol. 2017 May ; 17(5): 281–294
UTILITY OF V(D)J COMBINATION
39. T regulatory –cells (Treg)
• Approximately 10% of all CD4
• CD25+ CD4+ cells
• Expressions on Treg Cells:
1. Express FOXP3, a transcription factor: For
development and function
2. CD28 expressed on resting- T cells,
CTLA-4 expressed on T-cell surface after initial
TCR activation
3. High levels of IL-2 receptor alpha chain
(CD25)
Saturday, December 5, 2020 43
Kuby J et al, Textbook of Immunology, 8th Ed, 2019
Hypothesis for generation of Treg cells:
Thymic / Natural Treg
cells
(nTreg)
Peripheral / adaptive / inducible
(iTreg)
specific for self-peptides required for environmental
antigen/ allergen specific T cells
40. Saturday, December 5, 2020 44
Regulatory T Cells (Treg)
Nature Reviews Immunology, Volume 8, July 2008
Male D, Textbook of immunology , 8th ED, 2013
Functions:
• Suppresses Immune responses against pathogens, allergens, tumors, and allografts :
Peripheral Immunotolerance
• Protect fetus (semi-allografts): during pregnancy from immune rejection
Pivotal role in prevention of:
• autoimmune diseases like type 1 diabetes,
• chronic inflammatory diseases such as asthma and inflammatory bowel disease (IBD)
• Loss of function of Treg Cells: severe autoimmune inflammation in patients: IPEX Syndrome
(immunodysregulation, polyendocrinopathy, enteropathy, X-linked)
41. Inactivation of Traditional T cells by Treg cells
Saturday, December 5, 2020 46
TGF beta : Transforming growth factor beta
CTLA : Cytotoxic T cell lymphocyte associated protein
LAG : Lymphocyte-Activation gene
IDO : Indoleamine 2,3-dioxygenase
Vignali et al, Nature, 2008; 523-532
FOXP3
FOXP3
FOXP3
FOXP3
FOXP3
43. 1. Antigen sequestration
• Sequestered away from immunological system by physical and immunological barriers
• Breach in barrier elicits brisk response
– Sympathetic ophthalmia
– Formation of anti-sperm antibodies following vasectomy
Saturday, December 5, 2020 49Male D, Textbook of immunology , 8th Ed, 2013
45. Molecular Basis of Anergy Model
Saturday, December 5, 2020 51
• Receptors suppressing T cell Activation Signal: CTLA-4,
PD-1
• Transcription factors mediating anergy signals: NFAT1
,p27kip1, Tob
Mechanism:
• Suppression of IL-2 gene expression: Signal Block
• Lack of Co-stimulation
TCR-CD3-
Antigen-MHC
Complex
Kuby J et al, Textbook of Immunology, 8th Ed, 2019
46. CTLA-4 (Cytotoxic T-Lymphocyte-Associated Antigen 4 )
Molecular Basis
Saturday, December 5, 2020 52
IDO
End products of degraded tryptophan:
act directly on T-cells
IDO : Indoleamine 2,3-dioxygenase
• CTLA4 is a high affinity ligand for the costimulatory molecules CD80 and CD86
• Binds to B7-1/CD80 or B7-2/CD86 costimulatory molecules on APCs
• Critical Negative regulator of adaptive immune responses : Terminates T-cell
responses
APC
Treg
Molecular Basis of CTLA-4
Upregulation of IDO Catabolize tryptophan
Suppression of IL-2 gene expression
● Genetically engineered mice with deleted
CTLA4 :
Autoimmunity due to uncontrolled lymphocyte
activation with massive lymph node enlargement
● Polymorphism in CTLA-4 gene :
type 1 diabetes and Graves' disease
THERAPEUTIC APPLICATION
• Blocking CTLA-4 --> increased immune responses to
tumour
• Anti-CTLA-4 antibody(Cyclosporine, Tacrolimus,
Daclizumab, Basiliximab): approved for advance
melanomas
Schwartz JC et al, Nature. 2001;410(6828):604;Radvanyi LG et al, J Immunol. 1996;156(5):1788.
47. PD-1 (Programmed cell death 1)
Saturday, December 5, 2020 53
• Site of Action: Peripheral tissues
• Cellular Expression: Activated T cell
• Cells inhibited: CD8+ > CD4
• Molecular Signals: Inhibits kinase-dependent signals from CD28 and TCR (by recruiting and
activating phosphatase following binding to its ligands PDL-1 or PDL-2)
Recognises 2 ligands
1. PD-L1 : expressed on APCs and many other tissue
cells
2. PD-L2 : expressed mainly on APCs
Engagement with ligand
Inactivation of T cells
Abbas et al, Cellular and Molecular Immunology, 9th Ed
49. 3. Mechanism of Immune Suppression by Regulatory T cells
Regulatory T Cells Suppressor Mechanisms
Tr1, IL-10-induced IL-10, TGF-B, CTLA4, PDCD1
Th3 TGF-B, IL-10
CD4,CD25 (Negative)
Membrane TGF-B, CTLA4, PDCD1,GITR, IL-10
CD8,CD25,CD28 (Positive)
CD4 CD8 (Negative) Induction OF apoptosis
Γδ TCR IL-10, TGF-B
Saturday, December 5, 2020 55
Inhibit lymphocyte activation
and effector functions
Regulatory T cells suppress
immune mechanism via
suppressor mechanism
Kuby J et al, Textbook of Immunology, 8th ED, 2018
50. 4. Activation Induced Cell Death (AICD) of T-cells
Saturday, December 5, 2020 56
Activated T-cell express both:
• Fas(CD95): member of the TNF-receptor family and,
• FasL: membrane protein structurally homologous to
cytokine TNF
Death of excessively activated lymphocyte thus,
maintains lymphocyte homeostasis throughout life.
Male D, Textbook of immunology , Eighth edition , 2013
• Express a pro-apoptotic PROTEIN: Bim
• Absence of antiapoptotic expression: Bcl-2 and Bcl-x Unopposed Bim triggers
apoptosis by the p38MAPK-dependent mitochondria pathway
51. Saturday, December 5, 2020 57
1. Anergy: Internalisation of the BCR via reduced
expression of receptors for the cytokine B-cell
activating factor (BAFF)
2. B cell Intrinsic Mechanism: Dependence on T cell
help for high affinity isotype switched antibody
production
52. Saturday, December 5, 2020 58
Clinical Aspects of
Immunoreactivity and Immunotolerance
53. Immunological tolerance in Pregnancy
Saturday, December 5, 2020 59Guleria et al, J Immunol.2007; 178:3345-3351
IMMUNE PRIVILEDGE : FETUS
• Express MHC derived from both parents
• Peripheral tolerance of mother to fetus --> fetal survival
• Expression of FasL and FOXP3 transcription factor at fetal-maternal interface:
• clonal deletion of immune cells that recognize paternal Ags
• Cells of villous trophoblast lack expression of MHC class I, Downregulation of MHC-I molecules, HLA-A
& HLA-B
• Increase expression of inhibitory non-classical MHC molecule: HLA Ib genes, HLA-E, HLA-F, and HLA-
G
• Binds to inhibitory immune cell surface receptors: IL-4
• HLA-G inhibits Cytotoxic T cell responses Regulatory T-cells
• CD8+ T cell apoptosis induced by soluble HLA-G through the Fas/FasL pathway
• Interaction of HLA-G with KIR-related leukocyte Ig-like and CD85: DCs become tolerogenic,
Anergic T cells
54. Clinical
Gene Mutation Associated Disorders
AIRE APECED Syndrome: Autoimmune Polyendocrinopathy,
Candidiasis, Ectodermal Dystrophy.
Autosomal Recessive, autoimmune adrenal failure (Addison's
disease), hypoparathyroidism and chronic mucocutaneous
candidiasis.
FOXP3 IPEX Syndrome: : Immune dysregulation, polyendocrinopathy,
enteropathy, X-linked
Defects of V(D)J
recombination
SCID Syndrome: Severe combined immunodeficiency
Defects in TCR itself Nonlethal Combined Immunodeficiency
Polymorphisms: CD25
gene promoter region
Type 1 Diabetes, Multiple Sclerosis
Fas or FasL ALPS Syndrome: Autoimmune Lymphoproliferative Syndrome
Saturday, December 5, 2020 60
55. Immunology Is More
Than Just Vaccines and
Infectious Disease Saturday, December
5, 2020 61
Cytokine dysregulation;
Inappropriate MHC-expression;
Failure of Central/Peripheral
suppression
56. Dec Mar Jun Sep Dec Mar Jun Sep Dec Mar
1997
Jun
430 BC
15th
Century
1798 1881-
1885 1890
1940s
1950s:1900
1930s and
1940s
Thucydides:
Plague
Discovery
Chinese &
Turks:
Variolation
-small pox
crusts
Edward Jenner:
Protective effect
against smallpox
Pasteur:
Vaccines
against
Anthrax &
Rabies
Emil von
Behring &
Shibasaburo
Kitasato1st insights
into the
mech. of
immunity
Elvin
Kabat:
Used
Serum to
identify
γ-
globulins
Merrill
Chase:
Cellular
&
Humoral
Immunity
Paul
Ehrlich
Selective
Theory
Friedrich Breinl
& Felix
Haurowitz:
Instructional
Theory
A Historical Perspective of
Immunology
TIMELINE
Aaltonen &
Nagamene:
AIRE gene
discovery
Saturday, December 5, 2020 62