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Antigen

Lecture 2. Antigen. substances. Zhijian Cai, Ph.D Institute of immunology, ZJU caizj@zju.edu.cn. Introduction Antigenicity and specificity Requirements for immunogenicity Types of antigens Superantigen, immunological adjuvants and mitogen. Introduction.

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Antigen

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  1. Lecture 2 Antigen substances Zhijian Cai, Ph.D Institute of immunology, ZJU caizj@zju.edu.cn

  2. Introduction Antigenicity and specificity Requirements for immunogenicity Types of antigens Superantigen, immunological adjuvants and mitogen

  3. Introduction 1.Antigen (Ag) – A substance that induces a specific immune response and can specifically bind to antibodies and effect T and B cells. Alternative name - Immunogen 2.Property of Ag - immunogenicity and antigenicity Complete Ag has immunogenicity and antigenicity.

  4. Introduction 3.Hapten- A substance that is non-immunogenic but which can react with the products of a specific immune response. Haptens are small molecules which could never induce an immune response when administered by themselves but which can when coupled to a carrier molecule. Haptens have the property of antigenicity but not immunogenicity. 4. Tolerogen,allergen

  5. Antigenicity and specificity * Antigenicity The ability of a compound to bind with antibodies or with cells of the immune system. This binding is highly specific.

  6. Antigenicity and specificity * specificity 1. Antigenic determinant (epitope) - the portion of the antigen that binds specifically with the binding site of an antibody or a receptor on a lymphocyte. - the size of an epitope is approximately equivalent to 5-7 amino acids.

  7. Antigenicity and specificity description example One epitope haptens Many epitopes of the same specificity polysaccharides Many epitopes of different specificity proteins Reprensentation of some possible antigenic structures

  8. Antigenicity and specificity 2.structure of epitopes conformational determinant sequential or linear determinant

  9. B cell epitope Antigenic peptide Degradation T cell epitope T cell epitope Natural protein B cell epitope and T cell epitope 3. Epitopes recognized by B cells Epitopes recognized by T cells

  10. Antigenicity and specificity T cell epitopes B cell epitopes Receptor TCR BCR MHC necessary non-necessary Character linear short natural polypeptide peptide polysaccharides Size 8～12 aa(CD8+T) 5 ～15 aa 12～17aa(CD4+T) 5 ～7monosaccharides Type linear determinant conformational determinant ; linear determinant Location everywhere of Ag surface of Ag

  11. Antigenicity and specificity 4. Hapten-carrier effect

  12. Antigenicity and specificity *common antigen and cross-reaction

  13. Factors influencing immunogenicity A. Contribution of the Immunogen 1. Foreignness - The immune system normally discriminates between self and non-self such that only foreign molecules are immunogenic.

  14. Factors influencing immunogenicity A. Contribution of the Immunogen 2.Chemical Composition - In general, the more complex the substance is chemically the more immunogenic it will be. Carbohydrates（polysaccharides）：haptens Lipids：rarely immunogenic Nucleic acids：poor immunogens Proteins：virtually all proteins are immunogenic

  15. Factors influencing immunogenicity Contribution of the Immunogen 3. Size - There is not absolute size above which a substance will be immunogenic. In general, the larger the molecule the more immunogenic it is likely to be. high molecular weight：>6000 Da

  16. Factors influencing immunogenicity 4.Chemical Complexity- an increase in the chemical complexity of a compound is accompanied by an increase in its immunogenicity. Thus copolymers of several amino acids, such as polyglutamic, alanine, tend to be highly immunogenic. primary structure: amino acid sequence secondary structure :backbone of the polypeptide chain tertiary structure: three-dimensional configuration quaternary structure: more than one protein subunit

  17. Four structures of protein

  18. Factors influencing immunogenicity 5.Degradability and accessibility For antigen that activate T cells to stimulate immune responses, interactions with MHC molecules expressed on APCs must occur. 6. Physical form - In general particulate antigens are more immunogenic than soluble ones and denatured antigens more immunogenic than the native form.

  19. Factors influencing immunogenicity B. Contribution of the Biological System 1. Genetic Factors - Some substances are immunogenic in one species but not in another. Similarly, some substances are immunogenic in one individual but not in others (i.e.responders and non-responders). 2. Age - Age can also influence immunogenicity. Usually the very young and the very old have a diminished ability to mount and immune response in response to an immunogen.

  20. Factors influencing immunogenicity C.Method of Administration Dose - The dose of administration of an immunogen can influence its immunogenicity. 2. Route - Generally the subcutaneous route is better than the intravenous or intragastric routes. The route of antigen administration can also alter the nature of the response 3. Adjuvants

  21. Types of antigens Th: Thymus-dependent antigen(TD-Ag) Thymus-independent antigen(TI-Ag) Relative:Xenogenic antigen Allogenic antigen Autoantigen Heterophilic antigen

  22. Types of antigens TD-Ag T-dependent antigens are those that do not directly stimulate the production of antibody without the help of T cells. Proteins are T-dependent antigens.

  23. Types of antigens TI-Ag T-independent antigens are antigens which can directly stimulate the B cells to produce antibody without the requirement for T cell help In general,polysaccharides are T-independent antigens. The responses to these antigens differ from the responses to other antigens.

  24. Types of antigens TI-Ag T-independent antigens can be subdivided into Type 1 and Type 2 based on their ability to polyclonally activate B cells. Type 1 T independent antigens are polyclonal activators while Type 2 are not.

  25. (A) TI-1 Ag (B) TI-2 Ag

  26. Types of antigens Xenogenic Ag -An antigen found in more than one species.

  27. Types of antigens Allogenic Ag -individuals of a species differ in alleles (are allogeneic) and the antigenic diffences will cause an immune response to allografts. The antigens concerned are often of the MHC and are referred to as alloantigens.

  28. Types of antigens Autoantigen -The antigens of an organisms own cells and cell products are self antigens to the immune system of that organism. - Clones of immune cells reactive with self antigens are normally eliminated.

  29. Types of antigens Heterophilic Ag(Forssman antigen) - A cross-reacting antigen that appears in widely ranging species such as humans and bacteria. - Postinfectious glomerulonephritis: group A Streptococcus glomerular basement membrane

  30. Nonspecific immune activators Superantigen Adjuvant Mitogen

  31. Superantigen (SAg) When the immune system encounters a conventional TD-Ag, only a small fraction (1 in 106 -104) of the T cell population is able to recognize the antigen and become activated (monoclonal/oligoclonal response). However, there are some Ags which polyclonally activate some subtypes of the T cells (up to 25%). These Ags are called superantigens. Such as SEA~SEE, Mls (minor lymphocyte stimulating Ag)

  32. Types of SAgs Endogenous: Mls Exogenous: SE, etc. T cell SAgs: TCR SAgs: HSP TCR SAgs B cell SAgs: SPA, gp120 (HIV) bind BCR

  33. staphylococcal enterotoxin (SE) Superantigens bind directly to T-cell receptors and to MHC molecules.

  34. Types of SAgs B cell SAgs: SPA, gp120 (HIV) BCR cross-linking SPA (Staphylococcus aureus): 25%-46% B cell conventional Ag: 0.1% B cell

  35. SAgs in human diseases Food poisoning: SEA-SEE are potent gastrointestinal toxins responsible for staphylococcal food poisoning. Toxic shock syndrome (TSS): TSS toxin (TSST) is regarded as the primary causative agent for TSS which is mediated through TNF-.

  36. Streptococcal toxic shock syndrome (STSS): STSS, caused by S. pyogenes, is the most severe form of invasive streptococcal disease, with mortality rates of up to 50%. Streptococcal SAgs have implicated in STSS. Acute rheumatic fever (ARF): ARF is a cross-reactive immune response to the host’s cardiac tissue and it has been proposed that the reactive T cells might be driven by SAgs. Several novel streptococcal SAgs have been identified from ARF-associated serotypes.

  37. Autoimmune diseases:It has been proposed that SAgs might contribute to the pathogenesis of autoimmune disease by activating T cells that are specific for self antigens. SAgs could, under the right conditions, break the tolerance and suppression of autoreactive T cell clones and induce a state of autoimmunity. For example, administration of SEB to mice recovering from experimental autoimmune encephalomyelitis (EAE) triggered direct stimulation of the V3+ autoreactive MBP peptide specific T cells resulting in a rapid relapse of the disease.

  38. Adjuvants It is a substance which, when mixed with an immunogen, enhances the immune response against the immunogen. The use of adjuvants, however, is often hampered by undesirable side effects such as fever and inflammation. CFA, IFA, BCG, LPS, CpG, etc.

  39. Types of adjuvants Conventional: Freund adjuvants, including complete and incomplete Freund adjuvants. Novel: 1) Cytokine- Protein: IL-2 - Gene: IL-12, IFN- 2) Liposome;nanoparticle

  40. 3) CpG C: Cytosine (Cyt),G: Guanine (Gua) Immunological characteristic of CpG DNA Activate a variety of immune cells, including M, NK cell and B cell Induce cytokine production: IL-6, IL-12, IFN- Inhibit cell apoptosis and promote cell proliferation

  41. 4) HSP (heat shock protein) HSP100、HSP90、HSP70、HSP60 and small molecular HSP Function: serve as adjuvant or carrier for Ag, participate in synthesis, folding, assembly, transportation and degradation of proteins.

  42. Mitogen PHA (phytohemagglutinin, T, human) ConA (concanavalin A, T, mice) LPS (lipopolysaccharide, B,mice) SPA ( staphylococcus protein, B,human) PWM (pokeweed mitogen, T/B)

  43. summary Immunogenicity is the capacity of a compound to induce an immune response. Antigenicity refers to the ability of a compound to bind with antibodies or with the immune system. The smallest unit of antigen that is capable of binding with antibodies is called epitope. Adjuvants are substances that can accelerate,prolong and enhance the quality of specific immune responses. Superantigen are a class of antigens which cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release.

  44. Important items antigen; immunogenicity; immunoreactivity; hapten; epitope; squential epitope; conformational epitope; cross antigen; thymus dependent antigen, TD-Ag; thymus independent antigen, TI-Ag; heterophilic antigen; superantigen, SAg; adjuvant

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