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Transcript
Major Histocompatability Complex Molecular chaparones Hugh B. Fackrell 01/20/98 1 Major Histocompatability Complex Assigned Reading Content Outline Performance Ojectives – Key terms – Key Concepts Short Answer Questions 01/20/98 2 4 Assigned Reading Chapter: 9 pp 223-248 Janis Kuby’s Immunology 3rd Ed 01/20/98 3 5 Content Outline General Characteristics of MHC MHC Molecules & Genes – MHC-I – MHC-II – MHC-III Genomic maps of MHC Cellular Distribution of MHC Regulation of MHC Expression MHC and Immune Responsiveness MHC and Disease 01/20/98 4 6 General Characteristics of MHC MHC vs HLA Congenic mice Genetic Co dominance Location & function of MHC regions MHC haplotypes 01/20/98 5 7 MHC vs HLA MHC: Major Histocompatability complex – mouse genetic complex HLA: Human Leucocyte Antigen – human genetic complex Similar functions: different terms 01/20/98 6 MHC genes (mouse) Class 1 genes K D L R Qa Tla Class 2 genes A A E E Class 3 genes C4 Slp 01/20/98 7 61 HLA genes (human) HLA 1 B C A HLA 2 SB SB HLA 3 C4f C4S C2 Bf 01/20/98 8 62 MHC antigens codominate 01/20/98 9 53 Congenic Mice Two strains of mice that are genetically identical except at one locus developed by successive back crosses to one parent each progeny tested for specific difference if difference still present then back cross again 01/20/98 10 MHC: Assays Serotyping Mixed lymphocyte Reaction 01/20/98 36 11 Public vs Private Ag 01/20/98 58 12 Antibody production during Transplants 01/20/98 60 13 Antibodies during transplants (2) 01/20/98 59 14 Serological Tissue Typing 01/20/98 37 15 Mixed Lymphocyte Reaction 01/20/98 38 16 Mixed Lymphocyte Reaction 01/20/98 17 Haplotype Restricted Cytotoxicity 01/20/98 56 18 MHC Molecules & Genes Structure of MHC-I Structure of MHC-II Gene Organization Peptide Binding 01/20/98 19 8 MHC-I 01/20/98 20 9 MHCI Carbohydrates 01/20/98 40 21 MHC I: : 3D structure 01/20/98 41 22 HLA I: Structure 01/20/98 42 23 MHC I: Biological function 01/20/98 44 24 MHC-II Polymorphic Immunocytes Class II molecules 01/20/98 10 25 HLA 2: Structure 01/20/98 43 26 MHC II: Ag Presentation Detail 01/20/98 48 27 Idependent vs Associative recognition 01/20/98 55 28 MHCII: Function 01/20/98 50 29 MHCII: Biologogical function (2) 01/20/98 46 30 MHC II: Biological function 01/20/98 47 31 MHC II: Ag Presentation 01/20/98 49 32 01/20/98 13 33 MHC III Collection of genes associated with MHC Do not code for MHC I or MHC II Code for associated immunological molecules – complement – interferon – Tumour necrosis factor 01/20/98 34 Class III MHC Products Gene C2, C4a,C4b, Bf COL11A2 CYP21,CYP21P G7a/b HSP LMP2, LMP7 TAP1,TAP2 TNF-, TNF- 01/20/98 Encoded Protein Complement collagen Steroid 21-hydroxylases Valyl-tRNA synthetase Heat Shock Protein Proteasome-like subunits Peptide transports subunits Tumour Necrosis factor 35 Genomic maps of MHC MHC-I MHC-II MHC-III 01/20/98 11 36 01/20/98 37 Organization of Mouse Genes 01/20/98 52 38 Cellular Distribution of MHC 01/20/98 12 39 01/20/98 40 01/20/98 41 Regulation of MHC Expression 5’ promotor sequences Positive and negative control of transcription – CIITA-Transactivator – RFX Bare lymphocyte Syndrome 01/20/98 13 42 Regulation of MHC Expression Class I level of expression different in various cell types Class II- gene expression limited to certain cell types 01/20/98 13 43 MHC and Immune Responsiveness Determinant selection model Hole in the repertoire model 01/20/98 14 44 MHC and Disease 01/20/98 15 45 Distribution of MHC Antigens MHC I All nucleated cells & Platelets (mouse RBCs) MHC II lymphocytes, monocytes, macrophages 01/20/98 63 46 DONE!! 01/20/98 47 Performance Objectives 01/20/98 48 Key Terms alleles, alloantigens. bone marrow chimeras, Class I molecules, Class I regions, Class II molecules, Class II regions, Class III molecules, Class III regions, Determinant selection model, H-2 complex and its regions D region, I region, K region, L region, S region 01/20/98 17 49 hole in the repertoire models,locus, Immune response genes, congenic mice, Human Leukocyte Antigens, Major histocompatibility complex, MHC restriction, negative thymic selection positive thymic selection, public specificities, private specificities, region, Specificities, superantigens 01/20/98 18 50 Key Concepts Explain the connection between a trait and a gene using the specific example that MHC genes encode for molecules that allow specific immune responses. Describe the use of inbred mice for the elucidation of the genetics of the imune response Describe how congenic strains of mice are developed. 01/20/98 19 51 Describe and draw MHC-I molecules Describe the function of MHC-I molecules Describe and Draw MHC-II molecules Describe the function of MHC-II molecules 01/20/98 20 52 Compare the detailed differences in the structure of the aggreotope binding sites of MHC-I and MHC-II Describe the function of class III genes and in which cells they are expressed. Describe MHC restriction 01/20/98 21 53 Discuss the differences between MHC restriction of CD4+ T cells and MHC restriction of CD8+ T cells. Draw maps of either the MHC gene complex in mice or HLA gene complex in humans Describe how the collection of MHC genes of an individual dictates either the ability or inability of the animal to respond to a particular antigen 01/20/98 22 54 Describe an experiment that shows MHC restriction: – between T and B cells, – between T cells and macrophages – between cytotoxic T cells and virally infected cells. Discuss the biological relevance of MHC molecules MHC molecules exhibit a range of structural diversity at the species level that is roughly equivalent to the range of antibody diversity at the level of the individual animal. DISCUSS 01/20/98 23 55 Short Answers 01/20/98 56 Null cells are not MHC restricted. Explain. Even though the immune system rejects transplanted kidneys and hearts its function is not to protect us against grafts. Why do we need histocompatability antigens? If we do not need protection against attack from foreign organs and tissues, why are MHC-I molecules so polymorphic? 01/20/98 25 57 What is the connection between immunity and MHC genes.? Why are inbread/congenic mice important to immunlogical studies? Draw and label a diagram of a class I MHC molecule as it is found in the membrane. 01/20/98 26 58 Draw and label a diagram of a class II MHC molecule as it is found in the membrane. How is the polymorphism or diversity of MHC, different from the generation of diversity in antibodies? How do MHC-II molecules allow immune cells to communicate with each other? Why is this communication important? 01/20/98 27 59 What is the relationship between MHC- II molecules and Ir genes? Class III MHC molecules are not cell membrane proteins. What are they and what do they do? Describe an experiment to show MHC restricted cytotoxicity 01/20/98 28 60 T-cells do not recognize free antigen, as antibody receptors do. Speculate why? Briefly discuss MHC restriction. Describe and experiment that describes MHC restriction. Why do T cells have such an elaborate way of reacting with antigen? 01/20/98 29 61 Explain the following statement: "There is a direct relationship between an animal's MHC haplotype and its ability or inability to respond to a specific antigen." What is the difference between and F1 hybrid animal and a bone marrow chimera animal? What is the importance of a bone marrow chimera animal in immunological studies? Explain how the control of MHC restriction is the genetic basis for the functional specificity of T cells. 01/20/98 30 62 Describe T cell differentiation in the thymus using CD4 and CD8 markers. T cell receptor diversity results from gene rearrangements, but T cells are also MHC restricted. MHC restriction is not preprogrammed into T cells. Describe two possible selective processes that program T cells to be MHC restricted. Where do these processes occur? 01/20/98 31 63 T cells can react only with protein fragments. What is this process called? How does it occur? Which pathway leads to antigen interaction with MHC-I molecules? Which pathway leads to interaction with MHC-II molecules? 01/20/98 32 64 01/20/98 54 65 Evolution of MHCEpitopes 01/20/98 57 66