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Transcript
1 Antigens Hugh B. Fackrell 4/29/2017 2 Assigned Reading Content Outline Performance Objectives Key terms Key Concepts Short Answer Questions 4/29/2017 3 ASSIGNED READING Chapter 4 pp 87-106 4/29/2017 4 OUTLINE Immunogenicity vs antigenicity Factors that influence immunogenicity immunogen contributions biological system contributions Epitopes B cell epitopes T cell epitopes Haptens Mitogens 4/29/2017 5 Definitions Antigen - a substance recognized by T and B cell receptors Immunogen - a substance capable of eliciting immune response Hapten - a substance of low molecular weight, that can bind antibodies but induce response only if covalently attached to large carrier Klein, 1992 4/29/2017 6 Definitions (cont) Antigenic Determinant: Specific sequence of amino acids that combine with receptor Epitope: an antigenic determinant on the surface of a molecule Cryotope: An antigenic determinant that is buried within a molecule and thus is unavailable in the intact molecule 4/29/2017 7 Immunogen vs Antigen Immunogen Any compound that triggers the immune response Antigen Any compound that combines with the products of an immune response 4/29/2017 8 Factors Influencing Immunogenicity immunogen contributions biological system contributions 4/29/2017 9 Immunogen Contributions Chemical nature Chemical complexity Molecular size Conformation Foreigness 4/29/2017 10 Effects of Biological System on Immunogenicity Genotype Dose of Immunogen Route of Injection Adjuvants 4/29/2017 11 Genotypic Influences Immune Responsiveness Some strains of inbred mice respond to specific immunogen (high responders) Other strains do not (low responders) Hybrids of above have intermediate response Structure of MHC receptors on cell membrane 4/29/2017 12 MHC Receptors 4/29/2017 13 Dose of Immunogen Tolerance: Specific non response to an immunogen Dose dependent Too low- no effect Low dose: Tolerize T cell High dose: Tolerize B cells 4/29/2017 14 Mitcheson Tolerance Exp 200100- % Response Immunity Low Zone Tolerance High Zone Tolerance 0- log [antigen injected] 4/29/2017 15 Tolerogenic vs Immunogenic Immunogenicity antigens first processed by APC APC reacts with lymphocyte response Tolerogenicity antigens react directly with lymphocyte NO response Immunogenicity requires co stimulation 4/29/2017 16 Route of Injection Parenteral injection other than digestive tract intravenous, intradermal, sucutaneous, intramuscular, intraperitioneal Exposure to different lymphocyte populations intravenous - spleen subcutaneous- lymph nodes 4/29/2017 17 Adjuvants Substances that enhance immunogenicity of an antigen alum Freund’s ( contains Mycobacterium) Mechanisms prolong life of antigen enhance co-stimulatory signals nonspecific multiplication of lymphocyte granuloma formation 4/29/2017 18 Haptens Antigenic but not immunogenic small molecules eg DiNitroPhenol Flexible molecules eg gelatin When linked to a carrier molecule becomes immunogenic Hapten- Carrier conjugates Hapten immunodominant determinant 4/29/2017 19 Epitopes Size Specificity Affinity 4/29/2017 20 Construction of Epitope Continuous stretch of contiguous residues endowed with distinctive conformational features Discontinous group of residues that are non contiguous in the sequence but are brought together by the folding of the polypeptide chain Klein 1992 4/29/2017 21 B cell Epitopes 4/29/2017 22 Immunoglobulin: B cell receptor 4/29/2017 23 Antigen - Antibody binding Hydrogen bonds Electrostatic forces Van der Walls interactions Hydrophobic interactions 4/29/2017 24 4/29/2017 25 T cell Epitopes 4/29/2017 26 Mitogens 4/29/2017 27 The End 4/29/2017 28 Molecular Dissection of Proteinaceous Antigens Created Maria Sawicki Updated Hugh B. Fackrell Dec 1997 4/29/2017 29 X - Ray Crystallography Crystallized Antigen or Antigen - Antibody Complex Electron Density Map of the Molecule Three Dimensional Images 4/29/2017 30 Construction of Epitope Continuous stretch of contiguous residues endowed with distinctive conformational features Discontinous group of residues that are non contiguous in the sequence but are brought together by the folding of the polypeptide chain Klein 1992 4/29/2017 31 ANTIGEN RECOGNITION SYSTEMS Immunoglobulins intact antigen is presented with several conformational epitopes T cell receptors “processed antigen” is presented and can be recognized only in complex with Major HIstocompability Complex . 4/29/2017 32 Synthetic Peptides Overlapping Epitopes Immunodominance Benjamini ,1984 4/29/2017 33 Prediction of antigenicity Region accesibility Novotny 1988 Segmental Westhof et al 1984, Tainer et al 1985 Relative hydrophilicity Hoop and Woods1983, Hoop 1986 Chain termination Thorton and Sibanda 1983 Segmental mobility variability Jemmerson and Parerson 1985 4/29/2017 34 Epitope Mapping Cross-reactivity studies Native Protein and Peptide Fragments Synthetic Peptides Closely Related Proteins Van Renmortel, 1988 4/29/2017 35 Studies of Native Proteins and Peptide Fragments Conformational influences Native protein derivatives Overlapping peptide sequences Derivatives of active peptides Synthetic peptides Atassi, 1978 4/29/2017 36 The End 4/29/2017 37 Performance Objectives Key terms, concepts short answers 4/29/2017 38 KEY TERMS Accessibility, antigen, antigenic determinants, antigenic site mobility, antigenicity, continous (linear) determinants), discontinous (conformational) determinants epitopes, agreotopes, haptens, immunodominance, immunogen, immunogenicity 4/29/2017 39 KEY CONCEPTS Differentiate between and antigen's inductive and reactive abilities. Explain the factors that bestow immunogenicity on molecules Describe the discrete and distinctive sites on and antigen that are recognized by a B cell Immunoglobulin 4/29/2017 40 KEY CONCEPTS Describe the discrete and distinctive sites on and antigen that are recognized by a T cell receptor Describe the discrete and distinctive sites on and antigen that are recognized by the Major Histocompatability Complex Discuss some important characteristics of protein antigenic determinants 4/29/2017 41 SHORT ANSWER QUESTIONS 4/29/2017 42 Differentiate between immunogenicity and antigenicity. All immunogens are antigens but all antigens are not immunogens. Explain with the use of specific examples. An entire microbe or molecule does not induce and immune response. Explain. Irrespective of the number of epitopes that a molecule has, the immune response is biased and sees what it wants to see. Explain. 4/29/2017 43 Haptens are usually coupled to a carrier molecule before they are immunogenic. How can you demonstrate that the selected immunoglobulins are specific for the hapten and not for the carrier? As a corollory, would you expect ALL of the antibodies to be specific for the hapten? explain. 4/29/2017 44 Why is the definition of an antigen considered to be an operational definition. Differentiate between epitopes and agreotopes. Differentiate between epitopes recognized by B cell receptor and epitopes recognized by T cell receptors. 4/29/2017
