Major Histocompatability Complex

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Major Histocompatability Complex

• Molecular chaparones
• Hugh 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 Kubys 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-a, TNF-b

• 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
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