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Chapter 4 Antigen(Ag) 1 Contents PartⅠ Introduction PartⅡ Factors Affecting Immunogenicity PartⅢ Specificity and Cross-Reaction of Antigens PartⅣ Classification of Antigens PartⅤ Important Antigens in Medicine PartⅥ Superantigen and Adjuvants PartⅠ Introduction Ⅰ. Definition • Antigen(Ag): An antigen is a substance that can stimulate immune system to produce a specific immune response, and can react specifically with the products of the immune response in vitro or in vivo. • Products of the immune response: antibodies and/or effector lymphocytes. B cells Antibody T cells Effector T cells Ag Key points: • Stimulate immune system to produce a specific immune response. • React specifically with the products of the immune response in vitro or in vivo. Ⅱ. Properties of antigens 1. Immunogenicity: • An ability to stimulate the body to evoke a specific immune response. • Immunogens: substances with immunogenicity 2. Immunoreactivity: • Antigenicity • An ability to combine with corresponding Ab or sensitized T lymphocyte. 1.Immunogenicity: to induce the specific immune response. T Ag B T 2. Immunoreactivity: to combine with corresponding Ab or sensitized T lymphocyte T Ag B T Effector T cell Ⅲ. Complete antigen and hapten 1. Complete antigen: Both Immunogenicity and Immunoreactivity. 2. Hapten: Only Immunoreactivity. Hapten+carrier complete antigen Carrier: enhance the immunogenicity of hapten Ⅳ. Tolerogen and allergen • Tolerogen: substances to induce specific tolerance. • Allergen: substances to induce hypersensitivity (type I) Part Ⅱ Factors affecting immunogenicity Ⅰ. Factors related to antigens Ⅱ. Factors related to host Ⅲ. Methods of immunization Ⅰ. Factors related to antigens 1. Foreignness • According to Burnet, foreignness means substances which never contact with embryonic lymphocytes. Ⅰ. Factors related to antigens 1. Foreignness: “Non-self”substances and self components (1) Xeno-substances: various pathogens and their products, xeno-protein, etc. (2) Allo-substances: ABO blood type, HLA, etc. (3) Self components: - release of sequester antigen - degeneration 2. Physical and chemical properties (1) Molecular weight: reasonable large molecule( >10.0 kd) • • more stationary more surface structure for lymphocyte to recognize (2) Chemical composition and structure • Proteins >Polysaccharides >Nucleic Acids >Lipids aromatic ring ring > linear (3) Physical nature Polymer > monomer Particulate > Soluble Ⅱ. Factors related to host 1. Genetic background (Species, Individual) 2. Age, sex and healthy status Ⅲ. Pathway of immunization 1. Dosage of antigen 2. Times of injection 3. Ways: Intracutaneous>subcutaneous>muscle>intravenous >oral 4. Adjuvant: Certain substances which can enhance the Ir or change the type of Ir • What measures can be taken to increase the titers of antibody when preparing antibodies against sheep red blood cells in mice? Why? Part Ⅲ. Specificity and cross reaction of antigen Specificity • Exist in both immunogenecity and immunoreactivity • The basis of immunologic diagnosis and immunologic therapy Ⅰ. Antigenic determinant 1. Antigen determinants (epitope) are small particular chemical groups existing in antigen which combine with TCR/BCR or Ab. Polypeptide antigen----5-23 amino acid residues Polysaccharide antigen----5-7 monosaccharides Nuclear acid antigen----6-8 nucleotide 2. Antigenic valence: Total number of determinants which can be bound by antibody or antigenic receptor of lymphocytes. • Most natural antigens are polyvalence antigen. • Hapten is monovalence antigen. Ⅱ. Classification of antigenic determinant 1. According to the site and structure of Ag determinants Conformational determinants Sequential (or linear) determinants Conformational determinants Conformational determinants are formed by amino acid residues that aren’t in a sequence but become spatially juxtaposed in the folded protein. They are normally exist on the surface of antigen molecules. They are recognized by B cells or antibody. Sequential (or linear) determinants Epitopes formed by several adjacent amino acid residues are called linear determinants. They are exist on the surface of antigen molecules or inside molecules. They are mainly recognized by T cells, but some also can be recognized by B cells. B T/B 2. According to types of cells recognizing antigenic determinants T cell determinants (T cell epitopes): TCR B cell determinants (B cell epitopes): BCR Functional determinants Hidden determinants T cell epitope • Antigenic determinants recognized by T cells (TCR) • Composition: – Peptides – Sequential determinants(Exist in anywhere of Ag) • Processed (APC) • MHC presentation • Size – 8-23 residues B cell epitope • Antigenic determinants Recognized by B cells (BCR)and Ab • Composition: – Peptide, polysaccharides, nucleic acids – Conformational determinants or Sequential determinants (existed on the surface of Ag) Recognized directly No APC and MHC • Size – 5-15 residues B B/T 激活 降解 Comparison T cell epitope and B cell epitope T cell epitope Structure B cell epitope conformational epitope or linear epitope Receptor TCR BCR Features proteins proteins, polysaccharides Size 5-23 amino acid residues 5-15 amino acid residues or 5-7 monosaccharides or 5-8 nucleotides Location any part of antigen mostly exist on the surface of antigen MHC molecules yes no APC linear epitope yes no Functional determinant: epitope existed on the surface of Ag which can be recognized by BCR or combined with Ab easily. Immunodominant epitopes: specially important determinant. Hidden determinant: epitope existed inside of Ag which can not be recognized by BCR or combined with Ab easily. Ⅲ. Common antigen and cross reaction • Commom antigen: different Ag own the same epitope or their epitope have similar structure, these epitopes are called common antigen. • Species antigen: • Heterophilic antigen: common antigen among human, animal or microbes. •Cross reaction: reaction between the same Ab and different Ag with same similar determinants. B A C A A B + + + Anti-A serum Anti-A, B Ab ++ +++ + Anti-B serum Anti-A, C Ab +++ ++ • Mechanism of cross reaction: ---common Ag determinant. ---similar structure of Ag determinant. • Significance: ---Because there are some common antigen determinants between different microbes, so the antiserum against one kind of Ag can also react with another Ag and cause a cross reaction. ---In clinic, existence of cross reaction may lead to wrong diagnosis. Part Ⅳ. Classification of Ag Ⅰ. Ⅱ. Ⅲ. Ⅳ. According to immunogenicity of Ag According to dependence of T cells According to source of Ag Others Ⅰ. According to immunogenicity of Ag ----Complete Ag ----Hapten Ⅱ. According to dependence of T cells 1. TD-Ag (thymus dependent Ag ): TD-Ag can stimulate B cells to produce Ab only with the help of T cells. • Most TD-Ags are protein • More kinds of determinant, each kind with less number • Induce HI and CMI • Stimulate B cell to produce: IgG, IgM, IgA • Immune memory 2. TI-Ag • • • • • (thymus independent Ag) : stimulate B cells to produce Ab without the help of T cell. Most are polysaccharide There is more same repeat determinant Can not induce CMI Only induce B cell to produce IgM No memory Comparison of TD-Ag and TI-Ag TD-Ag TI-Ag Component Help of T cell Protein, more kinds Yes Polysaccharide, repeat epitope No Immune reponse HI and CMI HI Type of Ab more,IgG IgM Affinity of Ab High Low Immune memory Yes No Ⅲ. According to source of Ag • • • • Xenoantigen Alloantigen Autoantigen Heterophilic Ag Ⅳ. Others l Chemical component protein >polysacchride > nucleic acid >lipid l Natural Ag and artificial Ag Part Ⅴ. Important Ags in medicine Ⅰ. Heterogenous Ag (xeno-antigen) 1. Pathogens: Surface antigen “Vi” Ag Somatic Ag “O” Ag Flagellar Ag “H” Ag 2. Exotoxin and toxoid Exotoxin: Produced by G+ bacteria, Strong immunogenicity and pathogenicity. Toxoid: Under suitable conditions, exotoxin loss its toxicity without affecting its immunogenicity, then the exotoxin turned into toxoid. Anti-toxin Ⅱ. Immune serum: animal serum contains Abs after immunized by some Ag • Neutralize exotoxins • Serum disease Ⅲ. Heterophilic Ag (forssman Ag) -Common Ags are shared by different species -No specificity of species - Significance: immunopathology Diagnosis Ⅳ. Alloantigen 1. Antigen of red blood cell (blood typing) ABO system -very important in transfusion Rh system (in Chinese >99%RH+) -heamolytic disease of the newborn 2. Human leukocyte antigen, HLA system -relate to transplantation -very important in immune regulation Ⅴ. Autoantigen 1. Release of sequestered Ag 2. Modified of protein Ⅵ. Tumor antigen • Tumor specific Ag (TSA) --Only express on the tumor cells but normal cells • Tumor associated Ag (TAA) --Its express is high on tumor cells but low on normal cells, eg. AFP CEA Part Ⅵ. Superantigen and adjuvant Ⅰ. Superantigen (SAg) :Antigens that can non-specifically stimulate a plenty of T/B cells and induce a very strong Ir with a extremely low concentration. Conventional Antigen Superantigen The mechanism of SAg is different from that of Ags or mitogen. The mechanism of SAg is different from that of Ags or mitogen. • T cell SAg: exotoxin, protein of reverse transcript virus • B cell SAg: SPA(staphylococcal protein A) HIV:gp120 Ⅱ. Adjuvant ----Adjuvant is certain substance which can enhance the Ir or change the type of Ir when it is injected before or together with the antigens. Classification of adjuvant: Organic adjuvants: BCG Inorganic adjuvants: Al(OH)3 Synthesized adjuvants: polyI:C New adjuvants: nanomes, CpG,etc Common adjuvant: Incomplete Freund’s adjuvant (IFA) Complete Freund’s adjuvant (CFA) Mechanisms of adjuvant: • Change the chemical and physical characters of Ag • Improves the Ag process and presentation ability of macrophages • Stimulates proliferation of lymphocytes What you should know by the end of this lecture? Definition and characteristics of antigen Definition of antigenic determinants,conformational determinants and linear determinants Difference between T cell epitopes and B cell epitopes Definition of common antigen and cross reaction Difference between TD-Ag and TI-Ag How can you classify different Ag? what is TSA,TAA, hetreophilic Ag? Important antigens in medicine Adjuvant