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Chapter 7 Major Histocomptibility Complex (MHC) PowerPoint PPT Presentation


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Chapter 7 Major Histocomptibility Complex (MHC). Processing and presentation of exogenous and endogenous antigens. Antigenic peptides recognized by T cells form trimolecular complexes with a TCR and an MHC molecule. Class I MHC Peptide CD8 TCR T C cell.

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Chapter 7 Major Histocomptibility Complex (MHC)

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Chapter 7

Major Histocomptibility Complex (MHC)


Processing and presentation of

exogenous and endogenous antigens


Antigenic peptides recognized by T cells form trimolecular

complexes with a TCR and an MHC molecule

Class I MHC

Peptide CD8

TCR

TC cell

peptide


TCR and MHC-peptide

TCR

 peptide

 MHC


  • MHC molecules act as antigen-presenting

  • structure.

  • 2. MHC molecules expressed by an individual

  • influence the repertoire of antigens to which that individual’s TH cells and TC vells can respond.

  • 3. MHC partly determines the response of an individual to antigens of infectious organisms.

  • 4. MHC has been implicated in the susceptibility to disease and in the development of autoimmunity.


本章大綱:

1. General Organization and Inheritance of the

MHC

2. MHC Molecules and Genes

3. Genomic Map of MHC Genes

4. Cellular Distribution of MHC Molecules

5. Regulation of MHC Expression

6. MHC and Immune Responsiveness

7. MHC and Disease Susceptibility


General Organization and Inheritance of the MHC


Gorer (1930s):

1. Rejection of foreign tissue is the result of an

immune response to cell-surface molecules.

2. Identification of I, II, III and IV groups of genes.

Gorer and Snell (1940s & 1950s):

1. Antigens encoded by the genes in the group II took

part in the rejection of transplanted tumors and

other tissues.

2. Snell called these genes “histocompatibility genes”

(currently called H-2 genes)

3. Snell was awarded the Nobel Prize in 1980.


Human MHC: human leukocyte antigen

(HLA)

Mouse MHC: H-2


  • Class I MHC:

  • Expressed on the surface of nearly all nucleated cells; the major

  • function of the class I gene products is presentation of peptide

  • Ags to CD8+ T cells.

  • Class II MHC:

  • Expressed primarily on Ag-presenting cells (macrophages,

  • dendritic cells, and B cells), where they present processed

  • antigenic peptides to CD4+ T cells.

  • Class III MHC:

  • Generally encode various secreted proteins that have immune

  • functions, including components of the complement system and

  • molecules involved in inflammation.


  • The MHC loci are polymorphic:

  • Many alternative forms of the gene, or alleles, exist at

  • each locus.

  • The MHC loci are closely linked.

  • The recombination frequency within the H-2 complex

  • is only 0.5%.

  • Most individuals inherit the alleles encoded by these

  • closely linked loci as two sets, one from each parent.

  • Each set of alleles is referred to as a haplotype.

  • The MHC alleles are codominantly expressed;

  • that is, both maternal and paternal gene products

  • are expressed in the same cells.


Inheritance of MHC haplotypes


Acceptance or rejection of skin grafts is controlled by the MHC type of the inbred mice


Inheritance of HLA haplotype in a

hypothetical human family


Congenic MHC mouse strain

- Inbred mouse strains are syngeneic or identical at

all genetic loci.

- Two strains are congenic if they are genetically

identical except at a single locus or region.

- Congenic strains can be produced by a series of

crosses, backcrosses, and selections.


Production of congenic mouse strain

Strain A.B

Genetically identical to strain A except for the MHC locus or loci contributed by strain B.


Examples of recombinant congenic mouse strains generated during production of the B10.A strain from parental strain B10 (H-2b) and parental strain A (H-2a)


MHC Molecules and Genes


Class I molecule

(45 kDa)

(12 kDa)


Class II MHC molecule

(28 kDa)

(33 kDa)


Class I and class II molecules


Class I a chain, class II a, b chains and b2M are members of the Ig superfamily


3-D structure of the external domains of a human class I HLA molecule based on x-ray crystallographic analysis


Cleft: 25Å x 10Å x 11Å

can bind a peptide of 8-10 a.a.


Superimposition of the peptide-binding cleft

of class I and class II MHC molecules

Red: HLA-A2 (Class I)blue: HLA-DR1 (Class II)


Organization of class I MHC gene

= K


Organization of class II MHC gene

= IAb

IAb

IAa

= IAa


  • Peptide binding by MHC molecules

  • Peptide binding by class I and class II molecules does

  • not exhibit the fine specificity characteristic of Ag

  • binding by Ab and TCR.

  • A given MHC molecule can bind numerous different

  • peptides, and some peptides can bind to several

  • different MHC molecules.

  • The binding between a peptide and an MHC molecule

  • is often referred to as “promiscuous” (雜亂的).


Peptide-binding cleft is blocked

at both ends in class I molecules

8 – 10 amino acid residues, most commonly 9


Peptide-binding cleft is open

at both ends in class I molecules

13 – 18 amino acid residues


  • Binding affinity of MHC to peptides

  • The association constant KD of the peptide-MHC

  • molecule complex is approximately 10-6.

  • The rate of association is low, but the rate of

  • dissociation is even lower.

  • Thus, the peptide-MHC molecule association is very

  • stable under physiological conditions and most of the

  • MHC molecules expressed on the membrane of a cell

  • are associated with a peptide of self or nonself origin.


Class I MHC molecules bind peptides

and present them to CD8+ T cells

– cytosolic or endogenous processing pathway


Anchor residues in nonameric (9) peptides eluted from two class I MHC molecules

Usually

hydrophobic


Two different nonamers

can bind to the same H-2kb

Vesicular stomatitis Sendai virus

virus (VSV-8) peptide (SEV-9) nucleo-

protein


Conformational difference in bound

peptides of different lengths


Molecular models based on crystal structure of an

influenza virus antigenic peptide and an endogenous

peptide bound to a class I MHC molecule

influenza virus

endogenous


a1 and a2 domains of HLA-B27 and a bound antigenic peptide

peptide

water molecule


Class II MHC molecules bind peptides

and present them to CD4+ T cells

– endocytic or exogenous processing pathway


13 – 18 amino acid residues

Peptide-binding cleft is open

at both ends in class I molecules

13-18 a.a. residues

A central core of 13 a.a. determines the

ability of a peptide to bind class II.


Polymorphism of class I and class II molecules

- The diversity of the MHC within a species stems from

polymorphism, the presence of multiple alleles at a given

genetic locus within the species.

- The MHC possesses an extraordinarily large number of

different alleles at each locus and is one of the most

polymorphic genetic complexes known in higher vertebrates.

HLA-A 60 alleles H-2K 55 alleles

HLA-B 110 alleles H-2D 60 alleles

HLA-C 40 alleles

- The theoretical diversity possible for the mouse is:

100 (K) x 100 (IAa) x 100 (IAb) x 100 (IEa) x 100 (IEb) x 100 (D) = 1012


Linkage disequilibrium

Certain allelic combinations occur more frequently

than predicted is referred to as linkage disequilibrium.

[Hypothesis]:

1. Sufficientnumbers of generations have not elapsed.

2. Certain combinations of alleles are beneficial to the

individuals.

3. Crossovers are more frequent in certain DNA sequence

regions than in others.


Variability in the amino acid sequence

of allelic class I MHC molecules


Location of polymorphic amino acid residues

Most of the residues with significant polymorphism

are located in the peptide-binding cleft


Class III molecules are not membrane

proteins, are not related structurally to

class I and class II molecules, and have

no role in Ag presentation, although most

play some role in immune responses.

e.g., C2, C4a, C4b, factor B, 21-hydroxylase enzymes,

TNFa, TNFb, heat shock proteins (HSP)


Genetic Map of MHC Genes


Mouse H-2 is on the chromosome 17

Class I Nonclassical Class IIClass IIIClass I Nonclassical


Human HLA is on the chromosome 6

Class IINonclassical Class IIClass IIIClass I

Nonclassical


Cellular Distribution of

MHC Molecules


Cellular distribution of

MHC class I molecules

- In general, the classical MHC class I molecules are

expressed on most somatic cells.

- The highest level of class I molecules are expressed on

lymphocytes: 1 % of the total plasma membrane proteins

or 5 x 105 molecules / cell.

- Fibroblasts, muscle cells, hepatocytes and neural cells

express very low levels of class I molecules.

- A few cell types (e.g., neurons and sperm cells at certain

stages of differentiation) appear to lack class I MHC

molecules altogether.


Cellular distribution of

MHC class II molecules

- Class II molecules are expressed constitutively only by

Ag-presenting cells (APC), e.g., macrophages, dendritic

cells, and B cells.

- Thymic epithelial cells and some other cell types can be

induced to function as APC and then express class II

molecules under certain conditions.


Various MHC molecules expressed on APC of a heterozygous H-2k/d mouse


Nonclassical MHC class I and class II molecules

- Structurally similar to class I or class II molecules

- Less polymorphic

- Expressed at lower level

- Tissue distribution is more limited

- Functions not clear


The End


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