MHC
Large complex of tightly linked genes that encodes molecules involved in many aspects of the immune response.
HLA (humans) on chromosome 6
H-2(mice) on chromosome 17
DLA in dogs
XLA in Xenopus
etc.
To illustrate the size of the human HLA complex it is interesting to note that it is roughly the same size as the entire genome of E. coli.
The MHC is multigenic and multiallelic:
At each MHC locus there are multiple allelic forms possible. At the two most polymorphic regions (Class I and Class II) there are probably over 100 alleles at each loci.
Because there is such a low frequency of recombination, the MHC genes are inherited in 2 sets, one from each parent. Each of these sets is referred to as a haplotype. Therefore, siblings have a 1/4 probability of having the same MHC.
In outbred populations, individuals are usually heterozygous at most loci. So most individuals possess 2 different allelic forms of each of the MHC genes.
The MHC genes are co-dominantly expressed so an individual will express both maternal and paternal alleles in the same cell. Theoretically, there are more possible combinations of alleles than there are members of the species.
In inbred mice, each H-2 locus is homozygous, because the maternal and paternal haplotypes are identical. Certain inbred strains are prototypes H-2a, H-2b, H-2d, H-2k.
The superscript letter refers to the entire set of inherited alleles w/o referring to each allele individually.
It is possible for several different strains to have the same haplotype
CBA, C3H, and AKR are all H-2^k but they have different background genes.
H-2^k X H-2^b
F1 will be H-2^k/b
Congenic Mouse Strains
Two strains are congenic if they are gentically identical except at a single genetic locus or region. Such mice have been very useful in elucidating the contribution of MHC genes to specific diseases.
Three classes of molecules are encoded within the MHC:
Class I - present on all nucleated cells (except sperm and trophoblast)
Class II- present on macrophages, B cells, and dendritic cells
Class III- are not surface molecules, various proteins typically which have some immunological role (C2,C4, Tumor necrosis factor alpha and beta, various HSPs)
Human HLA region [Simplified version]
---DP--DQ--DR------------C4--C2--Bf----------------B--C--A---
DPa DPb Complement HLA-B
DQa DQb TNF a & b HLA-C
DRa DRb HSP proteins HLA-A
[class II] [class III] [class I]
Mouse H-2 region [Simplified version]
---K-----------I-A---I-E-----------------S---------------D--L----
H-2K Aa Ab Complement H-2D H-2L
Ea Eb C2, C4
TNF
HSPs
[class I] [class II] [class III] [class I]
The MHC is the most polymorphic gene complex known. The diversity of the MHC proteins (in particular the Class I and Class II MHC proteins) is due to this polymorphism.
Class I Molecules
Mouse [ H-2K,H-2D,H-2L]
Human [HLA-A, HLA-B, HLA-C]
The class I molecules are found on most nucleated cells. However, expression does vary between different cell types. The highest levels occur on lymphocytes while very low levels occur on liver hepatocytes. This may be one reason that liver transplants are among the most successful organ transplants.
See Structure of Class I MHC protein in text!!!
The protein is a heterodimer, but only one chain (the alpha chain) is encoded by the MHC.
Beta-2 microglobulin is encoded by a gene outside of the MHC. Has a mw of `12,000D. It is a small globular protein, very similar to an antibody constant region domain. NOT inserted into the cell membrane. Essential for stabilizing the structure of the a chain.
The alpha chain has a mw of ~45,000 D
There are three extracellular globular domains, a transmembrane domain and a cytoplasmic domain.
The Beta2- microglobulin and alpha 3 domains are associated by hydophobic interactions (NOT covalently bound to each other).
The alpha 3 domain and Beta-2microglobulin show a lot of homology with Ig constant region domains.
All individuals of the same species possess the same Beta-2 microglobulin, the alpha-3 domain is also pretty constant, but the alpha 1 and alpha 2 domains show extensive polymorphism. The alpha-1 and alpha-2 regions are recognized as foreign when tissue is transplanted between different individuals of the same species.
X Ray crystallographic analysis was published in1987 (Pamela Bjorkman). The complete analysis took her 8 years due to the challenge of obtaining a homogeneous preparation of the Class I alpha chain.
The peptide binding site is formed by the alpha 1 and alpha 2 domains of the alpha chain. The cleft is formed by a floor of 8 anti-parallel Beta sheets while the sides of the cleft are formed by 2 alpha helices. The cleft is closed on each end and it has been demonstrated that the peptide anchors at each of its end and bows out in the middle. The peptides which fit the cleft are between 8-10 amino acids in length, with the nonamer (9 amino acids) being the most common.
See figure of peptide binding cleft in the text.
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