Chapter 4 Antigen

Definitions of antigen Antigen: non-self substances which can combine with TCR or BCR or Ab and have the potential of inducing immune response. Antigen: Tolerogen: an antigen that induces immunological tolerance Allergen : an antigen that elicits an immediate hypersensitivity.

Section I Properties of Antigens and factors affecting immunogenicity

I. Properties of Ag  Immunogenicity An ability of antigen which can stimulate one individual to evoke a specific immune response (Ab or effector T cells).  Immunoreactivity (Antigenicity) An ability of antigen which can combine specifically with corresponding Ab or effector T lymphocyte.

Ag B cells Ab T cells effective T cells Immunogenicity Immunoreactivity

Hapten and carrier  Hapten: Only possess immunoreactivity  Carrier: enhance the immunogenicity of hapten  Complete antigen :possess both functions  Hapten +carrier ----complete antigen

II Factors of influencing immunogenicity 1. Factors related to antigens 1 ） Foreignness “Non-self ”substances: means substances which never contact with embryonic lymphocytes according to Burnet’s theory.  Xeno-substances (Various pathogens and their products, xeno- protein, etc.)  Allo-substances (ABO blood type, HLA, et al)  Self components - degeneration - release of sequester antigen - forbidden clone rejuvenate

Various clones Clone deletion Clone selection birth Burnet Clonal selection theory

2. Certain physical and chemical properties 1)Molecular weight: Reasonable large molecule( >10.0 kd) more stabilization  more surface structures for lymphocytes to recognize

2) chemical composition and structure Proteins >Polysaccharides >Nucleic Acids >Lipids aromatic ring ring > linear 3) physical nature polymer > monomer Particulate > Soluble Denatured > Native

II. Factors related to host 1. Inheritance (Species, Individual) 2. Age,Sex and healthy condition

III) Methods of immunity 1. Dosage of antigen, times of injection 2. Ways (subcutaneous>intravenous>oral) 3. Adjuvant Certain substance which can enhance the Ir or change the type of Ir

Section II. Specificity and cross reaction of antigen 1.Specificity and antigenic determinants Exist in both immunogenecity and immunoreactivity The basis of immunologic diagnosis and immunologic therapy

Specificity of Ag

2.Antigenic determinant 1)Antigen determinants (epitope) are small particular chemical groups existing in antigen which can be recognized by TCR/BCR or Ab. Polypeptide antigen amino acid residues Polysaccharide antigen monosaccharides Nuclear acid antigen nucleotides

Epitope: decide the specificity of the antigen a subtle change of antigenic determinant (characteristics, number and conformation) can influence the specificity of Ag. Antigen determinant is the combining site of Ag to Ab

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The chemical component, arrangement and conformation affect the specificity of antigen

2) Antigenic valence: Total number of determinants which can be bound by antibody or antigenic receptor of lymphocytes is called antigenic valence. Most natural antigens are polyvalence antigen. Hapen 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.

2. According to types of cells recognizing antigenic determinants  T cell determinants(T cell epitopes)  B cell determinants(B cell epitopes):  Functional determinants  Hidden or Sequestered determinants

T cell determinant  Antigenic Determinants recognized by T cells(TCR)  Composition:  Peptides  Sequential determinants(Exist in anywhere of Ag)  Processed  MHC presentation  Size  residues

B cell Determinant  Antigenic Determinants Recognized by B cells and Ab  Composition  peptide, polysaccharides, nucleic acids  Sequential determinants or Conformational determinants (existed on the surface of Ag)  Recognized directly by B cells  No MHC  Size: 5-7 residues

 Functional determinant : epitope existed on the surface of Ag which can be recognized by BCR or combined with Ab easily.  Hidden determinant: epitope existed inside of Ag which can not be recognized by BCR or combined with Ab easily. B cell determinants

Comparison T cell epitope and B cell epitope T cell epitope B cell epitope Structure linear epitope conformational epitope or linear epitope Receptor TCR BCR Nature proteins proteins, polysaccharides Size 5-23 amino acid residues 5-15 amino acid residues or 5-7 monosaccharides or 5-8 nucleotides Position any position in antigen mostly exist on the surface of antigen MHC molecules yes no Presentation

III. Common antigen and cross reaction  Common antigen : the same or similar determinants among various antigens are called common antigen.  Cross reaction: The antibodies induced by one kind of antigen can react with other antigen because of presence of common determinant between two antigens

A B Anti-A Anti-2 Anti-1 Anti-2 Anti-3 Anti-B

 Mechanism of cross reaction ---common Ag determinants ---similar structure of Ag determinants  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.

Section III. Classification of Ag I. Classification according to immunogenicity of the antigens  Complete Ag  Hapten

II. according to whether need the help of T cells when B cells produce Ab 1. TD-Ag (thymus dependent Ag ): TD-Ag can stimulate B cells to produce Ab with the help of T cells 2. TI-Ag (thymus independent Ag) : stimulate B cells to produce Ab without the help of T cell and MФ

1. TD-Ag (thymus dependent Ag ): TD-Ag can stimulate B cells to produce Ab only with the help of T cells ---most of TD-Ag are protein ----more kinds of determinants, less number of each kind ---stimulate B cell to produce :IgG, IgM, IgA ---capable of inducing CMI ---immune memory

2. TI-Ag (thymus independent Ag) : stimulate B cells to produce Ab without the help of T cell and MФ ---most are polysaccharide ---there is more same repeat determinants ---only induce B cell to produce IgM ---can not induce CMI ---no memory

CD40/CD40L B1 细胞 B2 细胞 Th 细胞 TI-1 抗原 TD-Ag TI and TD 抗 原 CD4 Antigen TI-Ag

III according to origin of antigens  xenoantigen  alloantigen  autoantigen

Section IV. Important Ags in medicine I. Pathogens and their products 1.Pathogens : Surface antigen “Vi” Ag Somatic Ag “O” Ag Flagellar Ag “H” Ag Pillus Ag

2. Exotoxin and toxoid Exotoxin Produced by G+ bacteria Strong immunogenicity and pathogenicity Toxoid exotoxin which losses its toxicity and maintains its immunogenicity under suitable conditions Tetanus toxoid

II. Immune serum of animal : animal serum contains Abs  Antibody activation: bind to antigen  Immunogenicity : hypersensitivity TAT: Tetanus anti-toxin

III. Heterophilic Ag (forssman Ag) ----common Ags are shared by different species no specificity of species Such as:  Forssman Ag: SRBC and guinea pig organs  Heart or kidney of human and streptococcus  O14 of E. coli and colonic mucos  Ox19 of proteus and R. typhi -- 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(HDNB) 2. Human leukocyte antigen, HLA system -relate to transplantation -very important in immune regulation

V. Autoantigen 1. Release of sequestered Ag 2. Modification of protein

VI. Tumor antigen  Tumor specific Ag, TSA --only express on the tumor cells but on normal cells  Tumor associated Ag,TAA -- Express highly on tumor cells but lowly on normal cells, eg. AFP CEA

Section V. Superantigen and adjuvant 1. Superantigen (SAg) :Substance that can non- specifically stimulate polyclonal T/B cells and induce a very strong immune response with a extremely low concentration

Superantigen Conventional Antigen

Superantigen Antigen The mechanism of SAg is different from that of Ags. TCR MHC

 T cell SAg : enterotoxin  B cell SAg: SPA (staphylococcal protein A) HIV:gp120

Biological actions of superantigen  1. activate immune response  2. Immune suppression  3. induce immune tolerance

Section VI Adjuvants

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 Common adjuvants: Incomplete Freund’s adjuvant complete Freund’s adjuvant

Classification of adjuvant organic adjuvants: BCG inorganic adjuvants: Al(OH) 3 synthesized adjuvants: polyI:C complex adjuvants

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, superantigen ?  Important antigens in medicine