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Mhc And Antigens

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  • 1. ANTIGENS Fe A. Bartolome, MD, FPASMAP Department of Microbiology Our Lady of Fatima University
  • 2. IMMUNOGENS
    • Protein or carbohydrate that challenges the immune system and that can initiate an immune response
    • Molecules that induce an immune response
    • Any substance that is capable of inducing an immune response (humoral or cellular or both)
  • 3. IMMUNOGENS
    • Chemical Nature
      • Proteins – majority of immunogens; may be pure proteins, glycoproteins or lipoproteins
      • Polysaccharides – pure polysaccharides or lipopolysaccharides
      • Lipids – non-immunogenic in general but may act as haptens
      • Nucleic acids – usually poorly immunogenic; become immunogenic when single-stranded or complexed with proteins
  • 4. ANTIGEN
    • Molecule that is recognized by specific antibody or T cells
    • Molecules that react with antibodies
    • Substance that is recognized by a particular immunoglobulin or T receptor and serve as target of an immune response
  • 5. ANTIGEN
    • PROPERTIES:
      • Foreignness
      • Chemical composition
      • Molecular size
      • Chemical complexity
      • Genetic constitution of host animal
      • Method of administration
  • 6. ANTIGEN
    • Types:
      • T-independent Antigens
        • Can directly stimulate B cells to produce antibodies
        • Polysaccharides in general
        • Generally more resistant to degradation  persist for longer periods of time  continue to stimulate immune system
  • 7. ANTIGEN
    • Types:
      • T-dependent Antigens
        • Do not directly stimulate antibody production; need help of T cells
        • Usually proteins
  • 8. HAPTEN
    • Molecule that is not immunogenic by itself but can react with specific antibody
    • A low MW substance which by itself cannot stimulate an immune response
    • Has to be bound to a carrier molecule (immunogenic molecule)
    • Cannot activate helper T cells  unable to bind to MHC proteins since are not polypeptides
    • Univalent  cannot activate B cells by themselves
  • 9. EPITOPE
    • Antigenic determinant
    • Actual molecular structure that interacts with a single antibody molecule or T cell receptor
    • Types:
      • Linear epitope – formed by a specific sequence
      • Conformational epitope – formed by a 3-D structure
  • 10. Schematic representation of two antibodies interacting with linear and conformational epitopes. a. Linear epitopes are short and continuous . After denaturation the linear epitopes may still be able to bind the antibody . b. Conformational epitopes are domains of proteins composed of specific regions of protein chains. After denaturation the discontinuous epitope can no longer bind the antibody .
  • 11. EPITOPE
    • B CELL EPITOPE
      • Region that is recognized by immunoglobulins
      • Size can encompass 3-20 amino acids or sugar residues
      • Limited to portions of the antigen that are accessible to the antibody
  • 12. EPITOPE B CELL EPITOPE Antigenic determinants are usually limited to those portions of the antigen that are accessible to antibodies shown in black for this iron-containing protein.
  • 13. EPITOPE
    • T CELL EPITOPE
      • Region recognized by T cell receptor
      • 8 – 15 amino acid residues long
      • recognized by T lymphocytes only after being processed and presented in association with an MHC protein  limited to portions of the antigen that can bind to MHC proteins
  • 14. ADJUVANT
    • Substance, which when mixed with an antigen, enhances the magnitude and duration of the immune response
    • Functions:
      • Prolong retention of immunogen
      • Increase the effective size of the immunogen
      • Stimulate local influx of macrophages or immune cells to the injection site
  • 15. ADJUVANT
    • EXAMPLES:
    • Complete Freund’s adjuvant
      • Heat-killed mycobacteria in mineral oil
    • Liposomes – defined lipid complexes
    • Bacterial cell wall components
    • Polymeric surfactants
    • Cholera toxin & E. coli lymphotoxin – potent adjuvants for IgA
  • 16. MAJOR HISTOCOMPATIBILITY COMPLEX
  • 17. MHC genes
    • Human leukocyte antigens (HLA)
    • Genes clustered in the MHC complex: short arm of chromosome 6
    • Characteristics:
      • Each person with two haplotypes
      • The genes are very diverse ( polymorphic )  many alleles ( polygenic )
      • Expression is co-dominant
    • Genes:
      • HLA-A, HLA-B, HLA-C  code for class I MHC proteins
      • HLA-D (DP, DQ, DR)  code for class II MHC proteins
  • 18. MHC glycoproteins
    • CLASS I MHC MOLECULES
      • Heterodimer  polymorphic  (heavy) chain non-covalently bound to a  2 -microglobulin (chr. 15)
      • Heavy chain composed of:
        • Hypervariable region – important for recognition of self and non-self
        • Constant region – CD8+ T cell binding site
      • Found on all nucleated cells and platelets
      • Present endogenous peptides
  • 19. Schematic representation depicting processing of antigens presented by class I MHC molecules. (1) Intracellular proteins are proteolytically degraded within proteasomes  (2) yields antigenic peptides of 9 – 11 amino acids  (3) antigenic peptides are transported into the ER  (4) bind to newly synthesized class I MHC molecules  (5) Class I MHC-antigenic peptide complexes are exported through the Golgi and to the cell surface, for presentation of antigenic peptide to CD8 + T cells. Cannon and Pate Reproductive Biology and Endocrinology 2003 1:93   doi:10.1186/1477-7827-1-93
  • 20. Calnexin (chaperone) assists in folding of MHC I proteins Calnexin released upon binding of β 2m with MHC I proteins Degradation of cytosolic proteins into peptides by proteosome. Peptides transported into the ER via TAP (transporter for antigenic peptides) Tapasin – assists in peptide loading or transfer from TAP to MHC I protein) ERAP (endopasmic reticulum aminopeptidase) plays major role in trimming peptides to 8-11 aa to fit into MHC antigen binding pocket.
  • 21.
    • CLASS II MHC MOLECULES
      • Coded for by HLA-D (DP,DQ,DR)
      • Heterodimer  noncovalently associated  chain and  chain
      • Composed of:
        • Hypervariable region – responsible for polymorphism
        • Constant region – CD4 T cell binding site
        • Invariant chain (Ii) – protect the binding site
      • Found on APC’s
      • Present exogenous antigens
  • 22. Schematic representation depicting processing of antigens presented by class II MHC molecules. (1) Extracellular and integral membrane proteins are internalized into endosomes via endocytosis  (2) Lysozomes fuse with endosomes. 3) Proteolytic degradation of endocytosed proteins resulting in the generation of antigenic peptides  (4) A specialized subcellualr organelle containing the class II MHC molecules, invariant chain, and DM fuses with the endolysozomal vesicle resulting in proteolytic degradation of invariant chain to CLIP. DM then catalyzes removal of CLIP, and the empty class II MHC molecules then bind antigenic peptides  (5) Class II MHC-antigenic peptide complexes are then exported to the cell surface, for presentation of antigenic peptide to CD4 + T cells. Cannon and Pate Reproductive Biology and Endocrinology 2003 1:93   doi:10.1186/1477-7827-1-93
  • 23. Exogenous proteins degraded into peptides via enzyme GILT (gamma interferon inducible lysosomal thiol reductase) Invariant chain blocks binding of endogenous peptides Invariant chain degraded in endosomal compartment leaving CLIP in antigen binding compartment Of MHC II protein Class II –associated invariant peptide HLA-DM & HLA-DO facilitate peptide loading on MHC II
  • 24.  
  • 25. MHC glycoproteins
    • CLASS III MHC MOLECULES
      • Between class I and class II; soluble proteins
      • Contain immunologically important genes encoding for:
        • Cytokines – TNF and lymphotoxin
        • Complement components – C2 and C4
      • Does not have genes that code for histocompatibility antigens
  • 26.
    • BIOLOGIC IMPORTANCE:
      • Antigen recognition by T cells
        • CD8 T cells  class I MHC molecules
        • CD4 T cells  class II MHC molecules
      • Autoimmune diseases occur in people who carry MHC genes (e.g. HLA-B27 in ankylosing spondylitis)
      • Success of organ transplants is determined by compatibility of MHC genes of donor and recipient.
  • 27. Important Features of Some Human MHC Gene Products Class I Class II Genetic loci (partial list) HLA-A, -B, and –C HLA-DP, -DQ, and – DR Polypeptide composition MW 45,000 +  2 M (MW 12,000)  chain,  chain, and Ii chain Cell distribution All nucleated somatic cells Antigen-presenting cells, activated T cells Present peptide antigens to CD8+ T cells CD4+ T cells Size of peptide bound 8 – 11 residues 10 – 30 or more residues
  • 28. Comparison of Class I and Class II MHC Proteins Feature Class I MHC Class II MHC Present antigen to CD4+ T cells No Yes Present antigen to CD8+ T cells Yes No Found on surface of all nucleated cells Yes No Found on surface of professional APCs Yes Yes Encoded by genes in the HLA locus Yes Yes Expression of genes is codominant Yes Yes Multiple alleles at each gene locus Yes Yes Composed of 2 peptides encoded in HLA locus No Yes Composed of one peptide encoded in the HLA locus & a  2-microglobulin Yes No