MHC Genes – H-2 Complex and HLA Complex

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What is HLA Complex?

  • The MHC in the human genome is known as the HLA complex (for human leukocyte antigen complex). The HLA complex encompasses approximately 3,500 kb on chromosome 6 and is composed of 12 main sections.
  • Each region contains dozens of genes, of which only a few are functional and the majority do not seem to be involved in antigen presentation.
  • The HLA-A, HLA-B, and HLA-C regions all belong to MHC class I. Each has a single gene expressing a human MHC class I α chain. The DP, DQ, and DR regions all belong to MHC class II.
  • Each has numerous functional genes encoding the α and β  chains of MHC class II. MHC class Ib proteins are encoded by a single gene in each of the HLA-E, -F, and -G regions, while MHC class IIb proteins are encoded by many genes in the DM and DO regions.
  • MHC class Ib and IIb proteins are structurally similar to MHC class I and II proteins, respectively, but are not directly involved in the presentation of antigens to T cells.
  • Therefore, MHC class Ib and IIb proteins are regarded as “non-classical” MHC molecules.
  • The MHC class III area is not known to encode any peptide-binding presentation molecules, although it does contain numerous genes involved in immunological responses, including as those encoding complement components, HSPs, and the cytokines TNF and lymphotoxin (LT).
HLA complex and H-2 complex

What is H-2 Complex?

  • The MHC in the mouse genome is referred to as the H-2 complex.
  • On chromosome 17, the H-2 complex spans 3000 kb and has 12 main areas.
  • The K, D, and L sections each contain a single gene encoding the mouse MHC class I α chain.
  • Each of the A and E sections encodes a single functional gene for an MHC class II α chain and one or more functional genes for an MHC class II β chain.
  • The S section of the H-2 complex encodes MHC class III proteins, including again complement proteins, HSPs, TNF, and LT.
  • The Q, T, and M sections of the H-2 complex contain genes for class Ib proteins, while the P, DO, and DM regions encode class IIb proteins. 

Detailed Organization Of The H-2 Complex

General Organization of the Major Histocompatibility Complex in Mice and Humans
General Organization of the Major Histocompatibility Complex in Mice and Humans

1. Murine MHC Class I Genes

  • Class I genes are also referred to as “traditional” MHC class I genes or class Ia genes.
  • The K region of chromosome 17, which is located close to the centromere, includes a single functional gene encoding the H-2K class I chain.
  • The D region contains one class I functional gene (the H-2D gene) and multiple pseudogenes (D2, D3, and D4).
  • In certain mouse strains, but not all, the L region has one gene encoding a functional chain.
  • Consequently, the majority of mice will express MHC class I chains from the K and D loci, but a minority will also express an MHC class I chain from the L locus.
  • Each of these chains can interact with 2m to produce a functioning MHC class I heterodimer on the cell surface, allowing for the appearance of up to six distinct MHC class I molecules (three from the maternal chromosome and three from the paternal chromosome).
  • In actuality, it is believed that changes in the regulatory elements that govern each locus result in a substantially smaller number of L chains being expressed compared to K and D chains, and a lower level of K expression than D expression. All MHC class I genes in both mice and humans share an identical exon–intron organisation.
  • Class I genes contain a 5 leader exon containing a 5 untranslated region and encoding a short signal peptide (cleaved off to form the mature MHC class I chain); three exons encoding domains 1, 2, and 3; an exon encoding a connecting peptide and the transmembrane region; and one or two exons comprising the cytoplasmic tail plus a 3 untranslated region.
  • Some researchers hypothesise that the various cytoplasmic tail exons may be indicative of as-yet-unidentified diverse functional roles played by different sections of the MHC tail.
  • In the exons encoding the 1 and 2 domains at sites involved in generating the peptide-binding groove, nucleotide sequence diversity predominates.

2. Murine 2-Microglobulin Gene

  • The other component of the MHC class I heterodimer is the polymorphic 2-microglobulin chain.
  • The mouse gene encoding 2m is located outside the MHC locus on chromosome 2 and is composed of three exons.
  • The first exon encodes a 5 untranslated region and the leader, whereas the second and third include the coding sequence. Additionally, the third exon contains a 3 untranslated region.

3. Murine MHC Class Ib Genes

  • Class Ib gene products are “non-classical” MHC molecules.
  • Although these proteins often resemble conventional MHC class I molecules, and many of them bind to 2m, they have significantly less polymorphism than class I molecules, are tissue-restricted in expression, and are not typically engaged in classical antigen presentation.
  • In reality, these genes make up the majority of MHC genes and are located in the Q, T, and M sections of around 2500 kb of DNA.
  • The roles of the products of these genes are the subject of extensive research.

4. Murine MHC Class II Genes

  • As stated previously, murine MHC class II and chains are encoded by genes located in the A and E sections of the H-2 complex.
  • The Aa and Ea genes code for the class II chains, while the Ab and Eb genes code for the class II chains.
  • With the exception of the Ea chain, each of these genes exhibits considerable variability at peptide-binding sites, whereas the Ea chain is very stable. There is an Eb2 gene, however it appears to be inactive.
  • The vast majority of MHC class II chain genes have the following structure: a 5 leader exon, two exons encoding the 1 and 2 domains, an exon encoding the transmembrane domain and a portion of the cytoplasmic tail, and a final exon containing the 3 untranslated region that completes the cytoplasmic tail.
  • MHC class II chain genes have a 5 leader exon, two exons encoding the 1 and 2 domains, an exon encoding the transmembrane domain and a portion of the cytoplasmic tail, and two more 3 exons comprising the 3 untranslated region.
  • Occasionally, the murine class II loci are referred to as the I-A and I-E loci, a historical holdover from early investigations into the effect of MHC haplotype on immunological response to a specific antigen. The letter “I” indicated the “immune response area” of the mouse MHC.
Detailed Organization of the Major Histocompatibility Complex
Detailed Organization of the Major Histocompatibility ComplexGenes located in the (A) murine H-2 complex and (B) human HLA complex. Class I, Ib, II, IIb, and III genes are color-coded and pseudogenes are not shown. In (A), all genes between Oa and TAP1 are considered to be located in the P region. In (B), all genes between DOA and DOB are considered to be in the DM and DO regions. The individual genotype shown has DRB1 and DRB3 although other DRB gene configurations are possible. See text for gene symbol definitions.

5. Murine MHC Class IIb Genes

  • The P area, which is situated between the K and A/E sections, contains a number of genes that resemble the functional A and E genes but are significantly less polymorphic.
  • These genes, identified as Oa, Ob, Ma, Mb1, and Mb2, have an unknown function (if any) and will not be further studied.

6. Murine Non-MHC Genes in the MHC

  • A group of genes necessary for the assembly of MHC class I molecules is located telomeric to the putative pseudogenes in the P region.
  • Before the resultant peptides can be linked with MHC class I and presented to CD8 T cells, endogenous proteins in the cytoplasm of a cell must be digested by a complex structure called a proteasome.
  • LMP2 and LMP7, two non-MHC class genes discovered at this site, encode components of the proteasome complex. LMP stands for “large multifunctional protease” and is pronounced “lamp.” TAP1 (“transporter in antigen processing 1”) and TAP2 encode proteins that create an intracellular pump that transfers freshly synthesised peptides from the cytosol to the rER.
  • The transported peptides subsequently bind to freshly generated MHC class I molecules and migrate to the cell surface.
Exon/Intron Structure of MHC Genes
Exon/Intron Structure of MHC Genes – Exon/intron structure of genes encoding (A) MHC class I chains and (B) MHC class II chains. The structures of the MHC genes are very similar in mice and humans. Schematics of the component protein chains are shown as reminders. L, leader sequence; UTR, untranslated region; CP, connecting peptide; TM, transmembrane region; C, cytoplasmic region; CS, coding sequence.

7. Murine MHC Class III Genes

  • Within the MHC, telomeric to the E region, is a collection of genes known as the MHC class III genes.
  • It does not appear that the class III genes encode molecules directly involved in antigen presentation. The class III region on mice was previously referred to as the “S” region because the complement component C4, isolated from serum, was localised to this region.
  • In reality, this region contains the genes encoding the C2, C4a, C4b, and Factor B complement components. Also present are the genes encoding the functional isoform of 21-hydroxylase (21-OH-A, derived from the CYP21 gene) and its non-functional isoform (21-OH-B, derived from the CYP21P pseudogene).
  • Heat shock protein genes, including the one encoding the HSP70 (“heat shock protein 70”) molecule, which may function during the protein degradation required for antigen presentation, are telomeric to these genes.
  • The TNFA and TNFB genes, which code for the cytokines TNF and lymphotoxin, are located between the HSP genes and the D region genes.

Detailed Organization Of The Hla Complex

1. Human MHC Class I Genes

  • HLA-A, -B, and -C are single genes encoding the human classical MHC class I chains, as described in previous sections.
  • These genes correspond to the functional K, D, and L genes of the mouse, respectively. Each of the HLA-A, -B, and -C genes on both parental chromosomes encodes a chain that can link with the invariant 2m molecule to generate MHC class I -2m heterodimers, indicating that six distinct MHC class I molecules can be co-dominantly expressed in a single cell.
  • As in the mouse, there are regulatory differences in the level of expression of distinct MHC genes.
  • 20–50% (depending on race) of humans reportedly do not express a functional HLA-C protein from one of the two alleles present at the HLA-C locus, despite possessing the gene.

2. Human 2-Microglobulin Gene

  • The 2m gene on human chromosome 15 is situated outside the major histocompatibility complex and has the same exon-intron structure as its murine homolog.

3. Human MHC Class Ib Genes

  • Class Ib genes include HLA-X, -E, -J, -G, and -F, and HFE (previously known as HLA-H), which encode “nonclassical” MHC products similar to those encoded by genes in the mouse Q, T, and M areas.
  • HFE [“rich in iron (Fe)”] appears to be important in iron absorption, although the precise roles of HLA-X, -E, -F, -G, and -J are uncertain.
  • They are structurally comparable to traditional class I genes but lack the diversity that comes with polymorphism. Combining with 2m and being surface-expressed suggests a role for some class Ib gene products in antigen presentation.
  • In addition to the HLA class Ib area, there are a lot of additional sequences that seem to be useless pseudogenes.

4. Human MHC Class II Genes

  • At least three of the five D families have distinct genes that encode the traditional MHC class II and chain genes.
  • It has been found that the HLA-DR genes are most similar to the murine H-2E genes, while the HLADQ genes are most similar to the murine H-2A genes.
  • Two genes, DPA1 and DPA2, in the HLA-DP area have the potential to encode chains; however, only DPA1 and DPA1 appear to be functional.
  • In contrast to the over a hundred alleles for DPB1, only about 25 for DPA1 have been discovered. The DQ family also has several genes that have the potential to encode chains, including DQA1, DQA2, DQB1, DQB2, and DQB3, however only DQA1 (25 alleles) and DQB1 (more than 50 alleles) really work.
  • Members of the DR family are exceptional in that they do not all have the same number of DRB loci on their chromosomes.
  • In all humans, a single, functioning gene called DRA accounts for the DR chain’s encoding. In contrast, nine distinct loci encoding chains, DRB1 through DRB9, have been uncovered among the human population.
  • When compared to the other DRB genes, DRB1 has an exceptionally high level of variability (over 354 alleles). While everybody possesses the DRB1 and DRB9 genes, they could also have one or more DRB loci picked at random from the DRB2 to DRB8 group.
  • DRB2, B6, B7, and B8 are all pseudogenes, and only DRB1, DRB3, DRB4, and DRB5 are fully functional.
  • One of the DRB3, DRB4, or DRB5 genes has been found in every analysed genotype so far. As a result of this structural and functional diversity, some people express chains generated from two genes in the DR regions of each chromosome: DRB1 and, if they have the gene, an extra chain derived from either DRB3, -B4, or -B5. It is possible for a single cell to express multiple MHC class II alleles from this area on a single chromosome.
  • Heterodimers (such as a class II molecule composed of HLA-DRA from the father and HLA-DRB1 from the mother) are formed when chains originating from the two chromosomes are combined.
  • Keep in mind, though, that DR chains tend to merge exclusively with other DR chains and rarely with DP or DQ chains.

5. Human MHC Class IIb Genes

  • Polypeptides encoded by genes in the HLA complex’s DO and DM sections are highly similar to those encoded by traditional MHC class II and chains.
  • Although these chains can and do form heterodimers, they are not directly engaged in antigen display and exhibit relatively little variability.
  • HLA-DM and HLA-DO both play key roles in regulating endocytic antigen processing.

6. Human Non-MHC Genes in the MHC

  • Similar to the mouse, genes involved in MHC class I molecule assembly are found in close proximity to class II genes.
  • Between the DP and DQ sections lie the genes for LMP2, LMP7, TAP1, and TAP2, which produce proteins with the same activities as their murine equivalents (see previous discussion).

7. Human Class III Genes

  • The class III region of the human MHC is located between the class II and class I genes, and it contains extra genes that play an important role in the immune system.
  • Similar (primarily complement-related and proinflammatory) genes to those found in the S region of the mouse MHC can be found in the human class III region.
  • The lymphotoxins in humans are encoded by the LTA and LTB genes.
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