1101/20/98 Major Histocompatability Complex Molecular chaparones Hugh B. Fackrell

2201/20/98 4 Major Histocompatability Complex l Assigned Reading l Content Outline l Performance Ojectives – Key terms – Key Concepts l Short Answer Questions

3301/20/98 5 Assigned Reading l Chapter: 9 pp l Janis Kuby’s Immunology 3rd Ed

4401/20/98 6 Content Outline l General Characteristics of MHC l MHC Molecules & Genes – MHC-I – MHC-II – MHC-III l Genomic maps of MHC l Cellular Distribution of MHC l Regulation of MHC Expression l MHC and Immune Responsiveness l MHC and Disease

5501/20/98 7 General Characteristics of MHC l MHC vs HLA l Congenic mice l Genetic Co dominance l Location & function of MHC regions l MHC haplotypes

6601/20/98 MHC vs HLA l MHC: Major Histocompatability complex –mouse genetic complex l HLA: Human Leucocyte Antigen –human genetic complex Similar functions: different terms

7701/20/98 61 MHC genes (mouse) l Class 1 genes K D L R Qa Tla Class 2 genes A  A  E  E  l Class 3 genes C4 Slp

8801/20/98 62 HLA genes (human) l HLA 1 B C A HLA 2 SB  SB  l HLA 3 C4f C4S C2 Bf

9901/20/98 53 MHC antigens codominate

10 01/20/98 Congenic Mice l Two strains of mice that are genetically identical except at one locus l developed by successive back crosses to one parent l each progeny tested for specific difference l if difference still present then back cross again

11 01/20/98 36 MHC: Assays l Serotyping l Mixed lymphocyte Reaction

12 01/20/98 58 Public vs Private Ag

13 01/20/98 60 Antibody production during Transplants

14 01/20/98 59 Antibodies during transplants (2)

15 01/20/98 37 Serological Tissue Typing

16 01/20/98 38 Mixed Lymphocyte Reaction

17 01/20/98 Mixed Lymphocyte Reaction

18 01/20/98 56 Haplotype Restricted Cytotoxicity

19 01/20/98 8 MHC Molecules & Genes l Structure of MHC-I l Structure of MHC-II l Gene Organization l Peptide Binding

20 01/20/98 9 MHC-I

21 01/20/98 40 MHCI Carbohydrates

22 01/20/98 41 MHC I: : 3D structure

23 01/20/98 42 HLA I: Structure

24 01/20/98 44 MHC I: Biological function

25 01/20/98 10 MHC-II l Polymorphic l Immunocytes l Class II molecules

26 01/20/98 43 HLA 2: Structure

27 01/20/98 48 MHC II: Ag Presentation Detail

28 01/20/98 55 Idependent vs Associative recognition

29 01/20/98 50 MHCII: Function

30 01/20/98 46 MHCII: Biologogical function (2)

31 01/20/98 47 MHC II: Biological function

32 01/20/98 49 MHC II: Ag Presentation

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34 01/20/98 MHC III l Collection of genes associated with MHC l Do not code for MHC I or MHC II l Code for associated immunological molecules –complement –interferon –Tumour necrosis factor

35 01/20/98 Class III MHC Products l Gene l C2, C4a,C4b, Bf l COL11A2 l CYP21,CYP21P l G7a/b l HSP l LMP2, LMP7 l TAP1,TAP2 TNF- , TNF-  l Encoded Protein l Complement l collagen l Steroid 21-hydroxylases l Valyl-tRNA synthetase l Heat Shock Protein l Proteasome-like subunits l Peptide transports subunits l Tumour Necrosis factor

36 01/20/98 11 Genomic maps of MHC l MHC-I l MHC-II l MHC-III

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38 01/20/98 52 Organization of Mouse Genes

39 01/20/98 12 Cellular Distribution of MHC

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42 01/20/98 13 Regulation of MHC Expression l 5’ promotor sequences l Positive and negative control of transcription –CIITA-Transactivator –RFX Bare lymphocyte Syndrome

43 01/20/98 13 Regulation of MHC Expression l Class I level of expression different in various cell types l Class II- gene expression limited to certain cell types

44 01/20/98 14 MHC and Immune Responsiveness l Determinant selection model l Hole in the repertoire model

45 01/20/98 15 MHC and Disease

46 01/20/98 63 Distribution of MHC Antigens l MHC I All nucleated cells & Platelets (mouse RBCs) l MHC II lymphocytes, monocytes, macrophages

47 01/20/98 DONE!!

48 01/20/98 Performance Objectives

49 01/20/98 17 Key Terms l alleles, alloantigens. bone marrow chimeras, Class I molecules, Class I regions, Class II molecules, l Class II regions, Class III molecules, Class III regions, Determinant selection model, l H-2 complex and its regions D region, I region, K region, L region, S region

50 01/20/98 18 l hole in the repertoire models,locus, Immune response genes, congenic mice, Human Leukocyte Antigens, Major histocompatibility complex, MHC restriction, negative thymic selection l positive thymic selection, public specificities, private specificities, region, Specificities, superantigens

51 01/20/98 19 Key Concepts l Explain the connection between a trait and a gene using the specific example that MHC genes encode for molecules that allow specific immune responses. l Describe the use of inbred mice for the elucidation of the genetics of the imune response l Describe how congenic strains of mice are developed.

52 01/20/98 20 l Describe and draw MHC-I molecules l Describe the function of MHC-I molecules l Describe and Draw MHC-II molecules l Describe the function of MHC-II molecules

53 01/20/98 21 l Compare the detailed differences in the structure of the aggreotope binding sites of MHC-I and MHC-II l Describe the function of class III genes and in which cells they are expressed. l Describe MHC restriction

54 01/20/98 22 l Discuss the differences between MHC restriction of CD4+ T cells and MHC restriction of CD8+ T cells. l Draw maps of either the MHC gene complex in mice or HLA gene complex in humans l 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

55 01/20/98 23 l 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. l Discuss the biological relevance of MHC molecules l 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

56 01/20/98 Short Answers

57 01/20/98 25 l Null cells are not MHC restricted. Explain. l 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? l If we do not need protection against attack from foreign organs and tissues, why are MHC-I molecules so polymorphic?

58 01/20/98 26 l What is the connection between immunity and MHC genes.? l Why are inbread/congenic mice important to immunlogical studies? l Draw and label a diagram of a class I MHC molecule as it is found in the membrane.

59 01/20/98 27 l Draw and label a diagram of a class II MHC molecule as it is found in the membrane. l How is the polymorphism or diversity of MHC, different from the generation of diversity in antibodies? l How do MHC-II molecules allow immune cells to communicate with each other? l Why is this communication important?

60 01/20/98 28 l What is the relationship between MHC- II molecules and Ir genes? l Class III MHC molecules are not cell membrane proteins. What are they and what do they do? l Describe an experiment to show MHC restricted cytotoxicity

61 01/20/98 29 l T-cells do not recognize free antigen, as antibody receptors do. Speculate why? l Briefly discuss MHC restriction. l Describe and experiment that describes MHC restriction. l Why do T cells have such an elaborate way of reacting with antigen?

62 01/20/98 30 l 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." l What is the difference between and F1 hybrid animal and a bone marrow chimera animal? l What is the importance of a bone marrow chimera animal in immunological studies? l Explain how the control of MHC restriction is the genetic basis for the functional specificity of T cells.

63 01/20/98 31 l Describe T cell differentiation in the thymus using CD4 and CD8 markers. l T cell receptor diversity results from gene rearrangements, but T cells are also MHC restricted. MHC restriction is not preprogrammed into T cells. l Describe two possible selective processes that program T cells to be MHC restricted. Where do these processes occur?

64 01/20/98 32 l T cells can react only with protein fragments. What is this process called? How does it occur? l Which pathway leads to antigen interaction with MHC-I molecules? l Which pathway leads to interaction with MHC-II molecules?

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66 01/20/98 57 Evolution of MHCEpitopes