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Major Histocompatability Complex

Molecular chaparonesHugh B. Fackrell

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Major Histocompatability Complex

Assigned Reading Content Outline Performance Ojectives

– Key terms– Key Concepts

Short Answer Questions

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Assigned Reading Chapter: 9 pp 223-248 Janis Kuby’s Immunology 3rd Ed

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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

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General Characteristics of MHC

MHC vs HLA Congenic mice Genetic Co dominance Location & function of MHC regions MHC haplotypes

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MHC vs HLA MHC: Major Histocompatability

complex– mouse genetic complex

HLA: Human Leucocyte Antigen– human genetic complex

Similar functions: different terms

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MHC genes (mouse)

Class 1 genes K D L R Qa Tla Class 2 genes A A E E Class 3 genes C4 Slp

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HLA genes (human)

HLA 1 B C A HLA 2 SB SB

HLA 3 C4f C4S C2 Bf

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MHC antigens codominate

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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

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MHC: Assays

Serotyping Mixed lymphocyte Reaction

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Public vs Private Ag

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Antibody production during Transplants

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Antibodies during transplants (2)

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Serological Tissue Typing

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Mixed Lymphocyte Reaction

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Mixed Lymphocyte Reaction

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Haplotype Restricted Cytotoxicity

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MHC Molecules & Genes Structure of MHC-I Structure of MHC-II Gene Organization Peptide Binding

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MHC-I

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MHCI Carbohydrates

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MHC I: : 3D structure

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HLA I: Structure

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MHC I: Biological function

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MHC-II Polymorphic Immunocytes Class II molecules

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HLA 2: Structure

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MHC II: Ag Presentation Detail

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Idependent vs Associative recognition

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MHCII: Function

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MHCII: Biologogical function (2)

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MHC II: Biological function

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MHC II: Ag Presentation

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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

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Class III MHC Products Gene C2, C4a,C4b, Bf COL11A2 CYP21,CYP21P G7a/b HSP LMP2, LMP7 TAP1,TAP2 TNF-, TNF-

Encoded Protein Complement collagen Steroid 21-hydroxylases Valyl-tRNA synthetase Heat Shock Protein Proteasome-like subunits Peptide transports subunits Tumour Necrosis factor

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Genomic maps of MHC MHC-I MHC-II MHC-III

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Organization of Mouse Genes

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Cellular Distribution of MHC

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Regulation of MHC Expression

5’ promotor sequences Positive and negative control of

transcription– CIITA-Transactivator– RFX

Bare lymphocyte Syndrome

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Regulation of MHC Expression

Class I level of expression different in various cell types

Class II- gene expression limited to certain cell types

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MHC and Immune Responsiveness

Determinant selection model Hole in the repertoire model

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MHC and Disease

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Distribution of MHC Antigens

MHC I All nucleated cells & Platelets (mouse RBCs)

MHC II lymphocytes, monocytes, macrophages

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DONE!!

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Performance Objectives

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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

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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

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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.

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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

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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

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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

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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

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Short Answers

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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?

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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.

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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?

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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

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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?

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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.

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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?

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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?

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Evolution of MHCEpitopes