U1 Ch3 - Antigens and MHC PDF

6/26/2024 Nature of Antigens and the Major Histocompatibility Complex Chapter 3 Preamble PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY. PowerPoints DO NOT cover the details needed for the Unit exam Each student is responsib...

6/26/2024 Nature of Antigens and the Major Histocompatibility Complex Chapter 3 Preamble PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY. PowerPoints DO NOT cover the details needed for the Unit exam Each student is responsible for READING the TEXTBOOK for details to answer the UNIT OBJECTIVES Unit Objectives are your study guide (not this PowerPoint) Test questions cover the details of UNIT OBJECTIVES found only in your Textbook! 1  6/26/2024 Factors influencing the immune response Traits of immunogens Chapter Overview Epitopes, haptens, and adjuvants Relationship of antigen to the host The major histocompatibility complex (MHC) and its role in the immune response Factors Influencing the Immune Response Older individuals—decreased response to Age antigenic stimulation Neonates—immune system not fully developed Overall Malnutrition Fatigue health Stress 2  6/26/2024 Factors Influencing the Immune Response Genetic capacity Route of inoculation Dose (predisposition) Intravenous Small amounts of Intramuscular antigen may not be Intradermal sufficient to activate the adaptive Subcutaneous immune response. Oral Very large doses can induce tolerance. Immunogens Versus Antigens Immunogen a substance that that reacts with antibody or sensitized cells but always triggers an immune response Antigen a substance that reacts with antibody or sensitized cells but may or may not be able to elicit an immune response. All immunogens are antigens but not all antigens are immunogens Terms are used interchangeably in most textbooks 3  6/26/2024 Traits of ImmunogensThat Influence the Immune Response Immunogen is a substance that triggers or stimulates an immune response of lymphocytes Immunogenicity depends on these four characteristics: 1. Macromolecular size 2. Chemical composition and complexity 3. Foreignness 4. Ability to be processed and presented by the MHC molecules The more unrelated a substance is to the host, the more successful it is as an immunogen. Proteins are the most effective immunogens, followed by polysaccharides. Traits of Immunogens Macromolecular size: At least 10,000 daltons to be recognized Most active are at least 100,000 daltons Some exceptions but generally the larger the weight the more potent the immunogen Chemical Composition: Proteins and Polysaccharides are the best immunogens Carbohydrates are less immunogenic – most often they are glycolipids or glycoproteins Many of the blood group antigens are made up of carbohydrate complexes 4  6/26/2024 Traits of Immunogens Foreignness: The immune system can distinguish between self and nonself Acquired from lymphocytes in the primary lymphoid organs. MHC (Major Histocompatibility Complex ) Must be subject to enzymatic digestion This allows creation of small peptides that can combine to the MHC molecules MHC molecules then present the substance to the T-cell lymphocytes Complexity of Proteins Is Based on Their Structure Levels of Protein Organization Primary Protein Structure Secondary Protein Structure Tertiary Protein Structure Quaternary Protein Structure 5  6/26/2024 Part of immunogen that is recognized by lymphocytes Each epitope can trigger a specific immune response Epitope Linear epitopes Sequential Example: amino acids following one another on a single polypeptide chain Conformational epitopes Result from folding of one or more chains Distant amino acids brought close together Epitopes recognized by B cells differ from those recognized by T cells Nature of Epitopes B cell activation is triggered by anything capable of cross-linking surface immunoglobulin molecules T cell is triggered only when the substance is part of a complex formed with MHC proteins 6  6/26/2024 B Cell Activation T Cell Activation Epitope Animation 7  6/26/2024 Haptens Small substances that are nonimmunogenic by themselves Create new antigenic determinants when combined with a carrier Example: Catechols from poison ivy bind to tissue proteins to produce contact dermatitis. When bound to carriers, contribute to the development of interconnected lattice that serves as the basis for precipitation and agglutination reactions Haptens Once antibody is formed, the hapten will elicit an immune response even if it is not combined with a carrier. Karl Landsteiner, a German scientist conducted the most famous study of haptens with the ABO blood groups. He discovered that antibodies recognize not just the chemical features of haptens but also the overall three-dimensional shape. 8  6/26/2024 Substances delivered simultaneously with an antigen to enhance the immune response; used in many vaccines Stimulate innate immune receptors Adjuvants Also prevent antigen from diffusing away from the site of inoculation Longer response time attracts more immune cells to the injection site and increases protective immunity. Relationship of Antigens to the Host Autoantigens Alloantigens Belong to the host From other members of Do not usually evoke an the host’s species immune response Examples: antigens If an immune response recognized in organ occurs, an autoimmune transplantation and condition is likely. blood transfusions 9  6/26/2024 Relationship of Antigens to the Host Heteroantigens From other species, such as animals, plants, or microorganisms Heteroantigens that exist in unrelated plants or animals but Heterophile are identical to or closely related in structure so that antibody to one antigen will cross-react with the other antigens Example: antigen from pneumococci bacteria cross-reacting with type A blood group antigen Major Histocompatibility Complex Molecules Determine whether transplanted tissue is histocompatible and accepted or recognized as foreign and rejected Linked to the genetic capability to mount an immune response Play a pivotal role in the development of humoral and cellular immunity Serve as carriers of peptide antigens for recognition by T cells 10  6/26/2024 Major Histocompatibility Complex Their main function is to bring antigen to the cell surface for recognition by T cells because only when antigen is combined with MHC molecules does T cell activation occur. Genes coding for MHC molecules are found on the short arm of Chromosome 6 Genes Coding for MHC Molecules 11  6/26/2024 Genes Coding for MHC Molecules Divided into three categories or classes: Class I: found on three different loci (designated as A, B, and C) Class II: found in the D region (designated as DR, DQ, and DP) Class III: found in a region between class I and II and codes for C4a, C4b, C2, and B Genes Coding for MHC Molecules The HLA system is the most polymorphic gene system in humans. Thousands of alleles – alternate forms of a gene that code for a slightly different variety of the same product – are found: More than 4,600 different HLA-A alleles, 5,500 HLA-B alleles, and 4,300 HLA- C alleles Each person has two HLA alleles of each type; linked genes are inherited (haplotype) 12  6/26/2024 Genes Coding for MHC Molecules Classes I and II are involved in antigen recognition; they influence the antigens to which T cells respond Class III is composed of secreted proteins that have an immune function, but they are not expressed on cell surfaces Class I MHC Molecules Expressed on all nucleated cells Differ in level of expression Highest on lymphocytes and myeloid cells Lowest or undetectable on liver hepatocytes, neural cells, muscle cells, and sperm 13  6/26/2024 Class I MHC Molecules (continued) Glycoprotein dimers made up of two noncovalently linked polypeptides: a chain with three domains b-2 microglobulin Class I MHC–Peptide Interaction Class I MHC molecules process endogenous antigens and present them to CD8+ cytotoxic T cells (Tc) It is the watchdog of viral, tumor, and certain parasitic antigens within the cell. 14  6/26/2024 Tc Recognize and CD8+ Tc bind to the antigen- Destroy Target Cells MHC Class I complex on the target cell surface. Tc release enzymes that destroy the target cell. Found primarily on APCs Include: Class II MHC Molecules B lymphocytes Monocytes Macrophages Dendritic cells Thymic epithelial cells 15  6/26/2024 Class II MHC Molecules (continued) DP, DQ, DR Major class II molecules Two noncovalently bound polypeptides that are encoded by separate genes in the MHC complex: a chain with two domains and b chain with two domains Class II MHC–Peptide Interaction Class II MHC molecules process exogenous antigens and present them to CD4+ T helper cells (Th) Class II alerts the CD4 T cells to the presence of foreign proteins outside the cell 16  6/26/2024 Th Assist Antibody Production CD4+ T helper cells stimulate B cells to divide and differentiate into antibody-producing plasma cells. Antigen Processing Animation 17  6/26/2024 Role of Class III Molecules in the Immune Response Class III – Not expressed on cell surfaces. It codes for complement proteins and cytokines called tumor necrosis factors α and β. It secretes proteins that have an immune function. Comparison of Class I and Class II MHC Molecules CLASS I MHC MOLECULES CLASS II MHC MOLECULES Cellular Distribution All nucleated cells B cells, monocytes, macrophages, dendritic cells, thymic epithelial cells Structure One a chain and b 2-microglobulin An a chain and a b chain Classes A, B, C DP, DQ, DR Size of Peptides Bound 8 to 11 amino acids 13 to 18 amino acids Nature of Peptide Binding Closed at both ends Open at both ends Cleft Interaction with T Cells Presents endogenous antigen to CD8+ T Presents exogenous antigen to cells CD4+ T cells 18  6/26/2024 Clinical Significance of MHC MHC classes I and II Important in tissue can induce graft transplant procedures rejection. Certain HLA types appear to play a role in development of autoimmune diseases. Association of HLA Alleles and Disease DISEASE SYMPTOMS HLA ALLELE STRENGTH OF ASSOCIATION Ankylosing Inflammation of the vertebrae of B27 +++ spondylitis the spine Celiac disease Diarrhea, weight loss, intolerance DQ2 +++ to gluten DQ8 + Rheumatoid Inflammation of multiple joints DR4 + arthritis Type 1 diabetes Increase in blood glucose because DQ8 ++ of destruction of insulin-producing DQ2 + cells +++ = very strong association, ++ = strong association, + = clear association, – = negative association. 19  6/26/2024 Summary Immunogens are macromolecules that elicit formation of immunoglobulins or sensitized lymphocytes in an immunocompetent host. An antigen denotes a substance that does not elicit a host immune response but reacts with antibody once it has been formed. Immunogenicity is influenced by factors such as age, health, and genetic makeup of the host, as well as molecular weight, complexity, and route of inoculation of the immunogen. Summary An epitope is a determinant site of an immunogen that is recognized by B or T cells. Haptens are small, nonimmunogenic substances that must be combined with a large carrier to provoke an immune response. Adjuvants are substances that can be mixed with an antigen to enhance the immune response. Autoantigens belong to the host. Alloantigens are from the same species as the host but are not identical to the host. Heteroantigens are from other species. Heterophile antigens exist in unrelated species, but their structure is so similar that antibody formed to one will cross-react with antigen from a different species. 20  6/26/2024 Summary The MHC encodes class I and class II molecules, which play a major role in antigen presentation to T cells. Class I and class II MHC molecules bind antigenic peptides within host cells and transport them to the plasma membrane, where the peptides can be recognized by T cells. Class I MHC molecules present endogenous antigens to CD8+ T cells, triggering a cytotoxic reaction. Class II MHC molecules present exogenous antigens to CD4+ T cells, which are T helper cells involved in antibody production. HLA, a highly polymorphic system, has thousands of different alleles in a population. Certain HLA types are associated with specific autoimmune disorders. Postamble READ the TEXTBOOK for the details to answer the UNIT OBJECTIVES. USE THE UNIT OBJECTIVES AS A STUDY GUIDE All test questions come from detailed material found in the TEXTBOOK (Not this PowerPoint) and relate back to the Unit Objectives 21