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Antigens

Antigens. Dr. Conrad Sept. 4, 2009. ANTIGENS Objectives: At the end of the lecture students will be able to:

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Antigens

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  1. Antigens Dr. Conrad Sept. 4, 2009

  2. ANTIGENS Objectives:At the end of the lecture students will be able to: 1. Provide working definitions for numerous immunologically important terms including: antigen, immunogen, allergen, tolerogen, adjuvant, antigenic determinants, epitope, hapten, avidity, and affinity. Your major challenge is to begin learning the language of immunology. 2. Give examples of different kinds of antigens and their attributes. Important attributes will include features required for immunogenicity, and factors that affect antigenic specificity. 3.. Explain the concept of haptens and carriers in relation to antigenic specificity and immunogenicity. 4. Relate antigenicity to vaccination strategies

  3. I. Introduction In order to understand antigen‑antibody reactions and the biological consequences of these reactions, some of the basic physical and chemical properties of both antigens and antibodies must be understood. We will begin with antigens. II. Antigens: In simplest terms, an antigen is a substance that can react with specific antibody. Related terms: immunogen (elicits the production of Ab), allergen, precipitinogen, tolerogen, etc ‑ note the gen. It is a bit confusing, but we also talk about antigens in reference to cell mediated immunity and cell mediated immunity typically does not involve any specific antibody .

  4. A. Chemical and physical makeup of Ags 1. Biological macromolecules (In order of importance): proteins > CHOs>nucleic acids> lipids >man‑made substances. 2. Charge ‑ not required but typically helpful. 3. Conformation ‑ Consider Myogloben as an example and relate conformation to the lock‑and‑key concept and involvement of primary, secondary, and tertiary structure. Note the different conformations that form the structure and the potential destructive effects of denaturation. 4. Stability ‑ e.g. RNA (because of RNase) and gelatin lacks a stable conformation. 5. Size ‑ >10,000 Daltons as a rule of thumb; a MW of 2,500 is a bit small (p. 615) 6. Solubility ‑ aggregated Ag Vs. soluble tolerogen 7. Metabolizability ‑ Sand, metal, glass won't work

  5. Sperm Whale Myogloben Crystalography 1969

  6. The lock‑and‑key concept

  7. A. Chemical and physical makeup of Ags 1. Biological macromolecules (In order of importance): proteins > CHOs>nucleic acids> lipids >man‑made substances. 2. Charge ‑ not required but typically helpful. 3. Conformation ‑ Consider Myogloben as an example and relate conformation to the lock‑and‑key concept and involvement of primary, secondary, and tertiary structure. Note the different conformations that form the structure and the potential destructive effects of denaturation. 4. Stability ‑ e.g. RNA (because of RNase) and gelatin lacks a stable conformation. 5. Size ‑ >10,000 Daltons as a rule of thumb; a MW of 2,500 is a bit small (p. 615) 6. Solubility ‑ aggregated Ag Vs. soluble tolerogen 7. Metabolizability ‑ Sand, metal, glass won't work

  8. B. Immunogenicity ‑‑ factors influencing: 1. Antigen must be foreign or sequestered ‑ Concept of self vs non‑self — Generally the more different from self the better the immunogen. Sequestered antigens may be self but they are hidden from the immune system. Examples include: the lens of the eye, thyroglobulin, sperm, CNS tissue, etc. These molecules are self but may behave as foreign or non-self. Necessity of danger signal or PAMP? 2. Dose of immunogen -- Moderate doses best; high or low doses can cause tolerance 3. Route of immunization -- Subcutaneous> intraperitoneal > intravenous>oral. Giving antigens orally can lead to tolerance. 4. Form of the immunogen -- Particulate better than soluble 5. Adjuvants ‑ Substances that improve the immune response when added to the immunogen. Freund's complete, alum, BCG, etc. The concept of “danger” may help explain the effect of adjuvants. The immune response serves best when it responds to something dangerous and adjuvants send danger signals. Adjuvants often contain microbial products or irritants that cause tissue damage – necrosis. 6 Interaction with MHC molecules - Peptides must bind MHC. Some molecules fail to bind MHC and are not immunogenic – animals with these MHC molecules are known as “non responders”.

  9. PAMP: Pathogen associated molecular pattern.

  10. PAMP recognition is a “danger signal” that results in activation of immune system – innate immune cells are attracted to area to try to destroy pathogen. Other cells (e.g. dendritic cells) are stimulated to move to secondary lymphoid sites – lymph nodes, spleen – and start the activation of the acquired immune system.

  11. Figure A-2

  12. Figure A-4

  13. Antigenic determinants/epitopes 1. Immunogens should be thought of as a mosaic of determinants. • 2. The number of determinants may be thought of as valence -- 4 for sperm whale myogloben, ~5 for albumin, ~40 for thyroglobulin, ~2500 for bacteriophage. 3. The greater the average hydrophilicity of local regions, the higher the likelihood that the region will be antigenic. 4. Immunodominance ‑ typically some molecules in a microorganism will elicit more antibody than others and some epitope on a given molecule will elicit more antibody than any other. • 5. Epitope size ‑ 3‑5 hexoses, 5‑7 amino acids • 6. Shape ‑the lock and key concept • 7. Haptens ‑ Could be considered isolated epitopes: Haptens alone will • not induce an immune response, they must be conjugated to a carrier (usually a protein). Appreciate that small drugs can become immunogenic.

  14. Antigenic determinants/epitopes -- continued 8. Epitopes – for antibody are generally surface associated, but can be buried and only seen after denaturation Conformational determinant – depends on 3D structure as aa can be quite far apart. Linear determinant – Since is composed of aa’s linked directly to each other can be seen both in native and denatured – but also frequently buried in native. Neoantigenic determinant – only seen after enzymatic change of protein – e.g. change from precursor to final protein • 9. Antibody reacts with intact antigen – epitopes on native structure are surface associated – could be either linear or conformational epitopes. • 10. T cells react with fragmented antigen – associated with MHC – therefore • buried vs surface does not apply to T cell epitopes.

  15. Sperm Whale Myogloben Crystalography 1969

  16. Figure 14-23 part 1 of 2

  17. Figure 14-23 part 2 of 2

  18. Figure 14-24 part 1 of 2

  19. Figure 14-25

  20. Antigens--summary Provide working definitions for numerous immunologically important terms including: antigen, immunogen, allergen, tolerogen, adjuvant, antigenic determinants, epitope, hapten, avidity, and affinity. Your major challenge is to begin learning the language of immunology. Give examples of different kinds of antigens and their attributes. Important attributes will include features required for immunogenicity, and factors that affect antigenic specificity. • Explain the concept of haptens and carriers in relation to antigenic specificity and immunogenicity and relate this to vaccine strategies.

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