Download Kuby`s Immunology

Major Histocompatability
Complex
Molecular chaparones
Hugh B. Fackrell
01/20/98
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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




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



Gene
C2, C4a,C4b, Bf
COL11A2
CYP21,CYP21P
G7a/b
HSP
LMP2, LMP7
TAP1,TAP2
TNF-, TNF-
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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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