Immunology 2nd Year/1st Semester Chapter 4 PDF

Immunology 2nd Year / 1st Semester Chapter 4 Antigen Major Histocompatibility Complex (MHC) TCR Dr. Lina ISMAIIL 2024-2025  Chapter 4 Immunogenicity: I...

Immunology 2nd Year / 1st Semester Chapter 4 Antigen Major Histocompatibility Complex (MHC) TCR Dr. Lina ISMAIIL 2024-2025  Chapter 4 Immunogenicity: It is the ability to induce a humoral and/or cell-mediated immune response. Immunology / 2024-2025  Chapter 4 Antigenicity Antigenicity: is the ability of a substance (antigen or Ag) to be specifically recognized by the immune system (B cells, T cells or both- BCR/antibodies and TCR) Antigen: any molecule recognized by the immune system, even if it does not stimulate it (human albumin-glucose) All immunogens are antigens but the reverse is not true (haptens) They are subgroups included in all Antigens Immunology / 2024-2025  Haptens Chapter 4 Substances, low molecular weight Unable to produce Antibodies Become immunogenic after coupling with large molecules (carrier) Immunology / 2024-2025  Tolerogens Chapter 4 substances that cause immune tolerance, i.e. an absence of immune reaction under specific conditions. This tolerance is host specific Immunology / 2024-2025  Tolerogens Chapter 4 Immunology / 2024-2025  Classification of antigens Chapter 4 A- Classification according to Strength 1- Strong immunogens 2- Weak immunogens 3- Haptens e.g. gold, copper, nickel, medicinal substance B. Classification according to nature 1- Soluble (Unfigured) antigens 2- Particulate (Figured) antigens Immunology / 2024-2025  Classification of antigens Chapter 4 C. Classification according to origin 1- Heterophilic antigen Crossreacting antigen that appears in widely ranging species such as humans and bacteria Ex: Forssman Ag 2- Heterologous antigen or xenoantigen An identical antigens found in the cells of different species. 3- Autoantigen: A normal protein or complex of proteins that is recognized by the immune system of patients suffering from a specific autoimmune disease. 4- Alloantigen antigens found in different members of the same species (the red blood cell antigens A and B are examples). Immunology / 2024-2025  Classification of antigens Chapter 4 D- The nature of the induced immune reactions Thymus-dependent antigens: T-cell dependent antigens are the type of antigens that require the help of T cells for the activation of B cells. Immunology / 2024-2025  Classification of antigens Chapter 4 D- The nature of the induced immune reactions - Thymus-independent antigens: T-independent (TI) antigens are typically polysaccharides with the ability to induce B-cell proliferation and antibody secretion in the absence of T cells. Immunology / 2024-2025  Antigenic sites Chapter 4 = epitopes = antigenic determinants = immunologically active regions of an immunogen, which bind to membrane receptors specific to this immunogen (TCR/Ab). An immunogen = several determinants, which may be different from each other, each capable of inducing the production of a specific antibody. In response to the introduction of this antigen → response against different epitopes: the antiserum obtained is said to be polyclonal. Immunology / 2024-2025  Concept of antigenic determinant Chapter 4 Antigenicity is based on the presence of the determining antigens: - Particular sites on the Antigen molecule which can unite with B and T Lymphocyte Receptors. - At the level of these antigenic determinants, Antibodies are fixed. - They constitute the active part of the molecule. 1- Antigenic determinants of carbohydrates - Certain polysaccharides have immunogenic power and several antigenic determinants - These are the same antigenic determinants which are repeated throughout the chain. - They cause the formation of numerous antibodies. 2- Antigenic determinants of proteins - Sequential determinants: an amino acid or a sequence of amino acids - Conformational determinants depend on the conformation of the particular areas of the molecule. Immunology / 2024-2025  Concept of antigenic determinant Chapter 4 3- Antigenic determinants of pure lipids: - are not immunogenic 4- Antigenic determinants of nucleic acids: - do not appear to have immunogenic power. - By coupling the nucleic acid with a carrier and in the presence of Freund's adjuvant, anti-DNA, anti-RNA Abs can be obtained Immunology / 2024-2025  Two types of antigen-specific receptors Chapter 4 B cells and T cells recognize different epitopes of the same antigen molecule Immunology / 2024-2025  Chapter 4 Epitope recognition / B –T Lymphocytes B Lymphocytes recognizes a non-degraded soluble Antigen / BCR The epitope site must therefore be accessible (“exposed” free surface of the immunogen) T Lymphocytes recognize an epitope/MHC complex The epitope site can therefore be “internal” to the immunogenic molecule: the T epitopes are moreover “linear internal”. Immunology / 2024-2025  Chapter 4 Antigenic recognition B lymphocytes (antibodies and BCR): recognition of macromolecules or small substances, soluble or associated with the cell surface. Immunology / 2024-2025 2023-2024  Chapter 4 Antigenic recognition T lymphocytes (TCR): peptide recognition presented by specialized molecules : MHC molecules (or HLA in humans) Immunology / 2024-2025  Properties of T cell epitopes Chapter 4 Tertiary TCR/Ag/MHC complex No fixation of a soluble Ag Necessary involvement of MHC molecules Antigen = Proteins +++, certain lipids. & glycolipids. Linear and internal peptides produced by antigen processing and association with MHC molecule Immunology / 2024-2025  Chapter 4 Major Histocompatibility Complex T lymphocytes recognize antigenic peptides presented by cell surface molecules → MHC (HLA in humans and H-2 in mice). - Complex → around a hundred genes coding for various products - Major → its products are at the origin of significant allogenic differences between individuals of the same species - Histocompatibility molecules → responsible for the phenomena of graft rejection between incompatible subjects. Immunology / 2024-2025  Chapter 4 Simplified organization of the MHC in humans (chr 6) located on the short arm of chromosome 6 subdivided into 3 regions including genes coding for products that differ in their location, structure and function: Immunology / 2024-2025  Chapter 4 1- The Class I region - Telomeric - contains HLA genes 2- The class II region - Centromeric - contains the HLA genes - Contains a series of genes coding for products which intervene in intracellular pathways of Antigenic presentation. 3- The class III region - intermediate - contains genes  coding for products involved in the immune response: (C3, C4A, C4B of C’, TNF-α,ß, heat shock protein)  which have nothing to do with the immune response. Immunology / 2024-2025  MHC class I Chapter 4  A polymorphic alpha chain - a hydrophilic extracellular region with 3 extracellular domains stabilized by disulfide bridges. Alpha chain: 45 kDa transmembrane glycoprotein  A hydrophobic transmembrane region (residues 284-307)  Short hydrophilic intracytoplasmic Ct segment (residues 308-312) and a small polypeptide chain, beta 2- microglobulin encoded on chromosome 15.  Beta 2-microglobulin non-covalently linked to class I glycoprotein a3 also carries an interaction site with the CD8 molecule expressed on the surface of cytotoxic T lymphocytes cells. Immunology / 2024-2025  MHC class II Chapter 4 Two different polypeptide chains  And  linked by non- covalent interaction Membrane glycoproteins that contain external domains a transmembrane segment and a cytoplasmic anchor segment The 1 And 1 domains form the antigen-binding cavity for the primed antigen Immunology / 2024-2025  MHC class I and II Chapter 4 Immunology / 2024-2025  Localization of HLA Antigens Chapter 4 Antigen class I Expressed on the majority of nucleated cells and on platelets Antigen class II: Much more restricted expression Expressed on Antigen-presenting cells, Lymphocyte B; macrophage Immunology / 2024-2025  Funtion of MHC Chapter 4 Role of HLA molecules in the presentation of endogenous and exogenous antigens Immunology / 2024-2025  Endogenous antigens: The cytosolic pathway Chapter 4 Within the RER membrane, a newly synthesized class I α chain associates with calnexin until ß2-microglobulin binds to the α chain. The class I α chain/ ß2-microglobulin heterodimer then binds to calreticulin and the TAP-associated protein tapasin. When a peptide delivered by TAP is bound to the class I molecule, folding of MHC class I is complete and it is released from the RER and transported through the Golgi to the surface of the cell. Immunology / 2024-2025  Endogenous antigens: The cytosolic pathway Chapter 4 Assembly and stabilization of class I MHC molecules Immunology / 2024-2025  Exogenous antigens: The endocytic pathway Chapter 4 Within the rough endoplasmic reticulum, a newly synthesized class II MHC molecule binds an invariant chain. The bound invariant chain prevents premature binding of peptides to the class II molecule and helps to direct the complex to endocytic compartments containing peptides derived from exogenous antigens. Digestion of the invariant chain leaves CLIP, a small fragment remaining in the binding groove of the class II MHC molecule. HLA-DM, a nonclassical MHC class II molecule expressed within endosomal compartments, mediates exchange of antigenic peptides for CLIP. The nonclassical class II molecule HLA-DO may act as a negative regulator of class II antigen processing by binding to HLA-DM and inhibiting its role in the dissociation of CLIP from class II molecules Immunology / 2024-2025  Exogenous antigens: The endocytic pathway Chapter 4 Generation of antigenic peptides in the endocytic processing pathway. Internalized exogenous antigen moves through several acidic compartments, in which it is degraded into peptides that ultimately associate with class II MHC molecules transported in vesicles from the Golgi complex. Immunology / 2024-2025  Role of HLA molecules in the presentation of endogenous and exogenous antigens Chapter 4 Proteins synthesized in the Proteins internalized by the cytosol cell proteins from intracellular Bacteria Cells or toxins microorganisms of an infected internalized by an APC cell Are prepared in the endocytic  Are prepared in the cytosol vesicle  Are charged on MHC class I Are loaded on MHC class II molecules molecules  Are presented to TC cells Are presented to TH cells (CD8+) (CD4+) Immunology / 2024-2025  T cell receptor complex: TCR-CD3 Chapter 4 Ig superfamily Two chains  and  Each contains two domains variable and constant TCR interacts with CD3 (complex consisting of a homodimer  associated with heterodimers and  and  ) Cytoplasmic tail of  responsible for signal transduction Immunology / 2024-2025  Double recognition of the MHC-peptide by the TCR Chapter 4 residue of the peptide establishing contact with the T lymphocyte Receptor of T lymphocytes polymorphic residue of the MHC molecule Peptide anchor residue MHC pocket of the MHC molecule Immunology / 2024-2025  Properties of MHC class I and class II molecules Chapter 4 MHC Class I MHC Class II Genetic location HLA-A, -B and -C DP, DQ and DR Structure a chain + b2 mglobuline a chain + b chain Expression On the surface of all nucleated Essentially on APCs cells Involved in the T cell CD8+ cytotoxiques T cell CD4+ presentation of the Ag to: Peptide source Proteins produced in the Extracellular proteins cytosol Polymorphic domains a + b2 a1+b1 Immunology / 2024-2025