HLA-DR is an
MHC class II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, ...
cell surface receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...
encoded by the
human leukocyte antigen
The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
complex on chromosome 6 region 6p21.31. The complex of HLA-DR (Human Leukocyte Antigen – DR isotype) and peptide, generally between 9 and 30 amino acids in length, constitutes a
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
for the T-cell receptor (TCR). HLA (
human leukocyte antigens
The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
) were originally defined as cell surface antigens that mediate
graft-versus-host disease
Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.
White blood cells of the donor's immune system which remain wit ...
. Identification of these antigens has led to greater success and longevity in organ transplant.
Antigens most responsible for graft loss are HLA-DR (first six months),
HLA-B
HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) compl ...
(first two years), and
HLA-A
HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of ...
(long-term survival).
Good matching of these antigens between host and donor is most critical for achieving graft survival.
HLA-DR is also involved in several autoimmune conditions, disease susceptibility and disease resistance. It is also closely linked to
HLA-DQ
HLA-DQ (DQ) is a cell surface receptor protein found on antigen-presenting cells. It is an αβ heterodimer of type MHC class II. The α and β chains are encoded by two loci, HLA-DQA1 and HLA-DQB1, that are adjacent to each other on chromos ...
and this linkage often makes it difficult to resolve the more causative factor in disease.
HLA-DR molecules are upregulated in response to signalling. In the instance of an infection, the peptide (such as the staphylococcal enterotoxin I peptide) is bound into a DR molecule and presented to a few of a great many T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation.
Function
The primary function of HLA-DR is to present peptide antigens, potentially foreign in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually lead to the production of antibodies against the same peptide antigen.
Antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
s (macrophages, B-cells and
dendritic cells
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
) are the cells in which DR are typically found. Increased abundance of DR 'antigen' on the cell surface is often in response to stimulation, and, therefore, DR is also a marker for immune stimulation.
Structure
HLA-DR is an αβ
heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
,
cell surface receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...
, each subunit of which contains two extracellular domains, a membrane-spanning domain and a cytoplasmic tail. Both α and β chains are anchored in the membrane. The N-terminal domain of the mature protein forms an alpha-helix that constitutes the exposed part of the binding groove, the C-terminal cytoplasmic region interact with the other chain forming a beta-sheet under the binding groove spanning to the cell membrane. The majority of the peptide contact positions are in the first 80 residues of each chain.
Genetics
The
genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
of HLA-DR is complex. HLA-DR is encoded by several loci and several 'genes' of different function at each locus. The DR α-chain is encoded by the
HLA-DRA
HLA class II histocompatibility antigen, DR alpha chain is a protein that in humans is encoded by the HLA-DRA gene. HLA-DRA encodes the alpha subunit of HLA-DR. Unlike the alpha chains of other Human MHC class II molecules, the alpha subunit is pra ...
locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award' ...
. Unlike the other DR loci, functional variation in mature DRA gene products is absent. (Note: see table ''Number of Variant Alleles HLA-DR Loci''- reduces the potential functional combinations from ~1400 to ~400 (
able is not exact because new alleles are continually being added; not all new alleles are functional variants of the mature subunits.
The DR β-chain
is encoded by 4 loci, however no more
than 3 functional loci are present in a single individual, and no more than two on a single chromosome. Sometimes an individual may only possess 2 copies of the same locus,
DRB1*. The
HLA-DRB1
HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
locus is ubiquitous and encodes a very large number of functionally variable gene products (
HLA-DR1
HLA-DR1 (DR1) is a HLA- DR serotype that recognizes the DRB1*01 gene products. It has been observed to be common among centenarians.
Serology
The serology for the most common DR1 alleles is excellent. The serology for alleles , , , , , , and ...
to
HLA-DR17
HLA-DR17 (DR17) is an HLA- DR serotype that recognizes the DRB1*0301 and *0304 gene products. DR17 is found at high frequency in Western Europe (such as Western Ireland, N. Spain, Sardinia). DR17 is part of the broader antigen group HLA-DR3 and i ...
). The HLA-DRB3 locus encodes the
HLA-DR52
HLA-DR52 is an HLA-DR serotype that recognizes gene products of HLA-DRB3 locus. Three allele groups can produce 35 isoforms.
DRB3, DRB4, and DRB5 are minor DR beta-encoding loci, and they have been recognized as having distinct evolution, having d ...
specificity, is moderately variable and is variably associated with certain
HLA-DRB1
HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
types. The HLA-DRB4 locus encodes the
HLA-DR53
HLA-DR53 is an HLA-DR serotype that recognizes gene products of HLA-DRB4 locus. There are 13 alleles at this locus that encode 7 proteins.
DRB3, DRB4, and DRB5 are minor DR beta encoding loci, they have been recognized as having distinct evolution ...
specificity, has some variation, and is associated with certain
HLA-DRB1
HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
types. The HLA-DRB5 locus encodes the
HLA-DR51
HLA-DR51 is a HLA-DR serotype that recognizes the antigens encoded by the minor DR locus HLA-DRB5.
DRB3, DRB4, and DRB5 are minor DR beta encoding loci, they have been recognized as having distinct evolution, having diverged from DRB1 approximate ...
specificity, which is typically invariable, and is linked to the
HLA-DR2
HLA-DR2 (DR2) of the HLA- DR serotype system, is a broad antigen serotype that is now preferentially covered by HLA-DR15 and HLA-DR16 serotype group. This serotype primarily recognizes gene products of the HLA-DRB1*15 and HLA-DRB1*16 allele gro ...
types.
*linkage (See Table)
**
DQA1 and DQB1
***Linkage disequilibrium exists for many
DR-DQ types.
**Nomenclature issues. Some older studies may refer to DR15 or 16 as DR2 and DQ5 and DQ6 as DQ1 therefore a haplotype DR2-DQ1 is usually referring to DR15-DQ6 but could be referring to DR16-DQ5. DR5 is used to refer to DR11 and DR12, in which case DQ3 might be used. In these instances DQ3 almost always can be interpreted as DQ7, but DR5 is most often DR11 and less frequently DR12. Similar issues exist for DR6 versus DR13 and DR14. DR6-DQ1 can refer to either DR13-DQ6 or less frequently DR14-DQ5, but DR6-DQ3 or DR6-DQ7 generally refers to DR13-DQ7. Even older literature has more confusing designations. By looking at the change of disease association with improved testing we can see how HLA nomenclature has evolved over time.
Evolution and allele frequencies
There is a high level of allelic diversity at HLA DRB1, it is second only to HLA-B locus in number of allelic variants. These two loci are highest sequence variation rate within human genome. This means
HLA-DRB1
HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
is rapidly evolving, much more rapidly than almost all other protein encoding loci. Much of the variation at HLA DRB1 occurs at peptide contact positions in the binding groove, as a result many of the alleles alter the way the DR binds peptide ligands and changes the repertoire each receptor can bind.
This means that most of the changes are functional in nature, and therefore are under selection. In the HLA region, genes are under heterozygous or balancing selection, although certain alleles appear to be under positive or negative selection, either in the past or present
HLA generally evolve through a process of
gene conversion
Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion event. Gene conversion can be either allelic, meaning that one allele of the same gene replaces a ...
, which is a form of short distance or 'abortive'
genetic recombination
Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryo ...
. Functional motifs in genes are exchanged to form new alleles, and frequently new, functionally different DR
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
s. HLA-DR represents an extreme example of this. A survey of X-linked loci reveals that most human loci have undergone fixation within the last 600,000 years, and diploid loci have undergone significant proportion of fixation in that period of time.
The level of deep branching at X-linked loci indicates loci were close to fixation or fixed at the end of the human
population bottleneck
A population bottleneck or genetic bottleneck is a sharp reduction in the size of a population due to environmental events such as famines, earthquakes, floods, fires, disease, and droughts; or human activities such as specicide, widespread violen ...
100,000 to 150,000 years ago. The HLA-DR locus represents a major exception to this observation. Based on distribution of major groupings in the human population it is possible to assert that more than a dozen major variants survived the population bottleneck. This observation is supported by the concept of a heterozygous selection coefficient operating on the HLA-DR, and at the
HLA-DRB1
HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
locus to a greater degree relative to
HLA-DQB1
Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene. The protein encoded by this gene is one of two proteins that are required to form the DQ het ...
and
HLA-DPB1
HLA class II histocompatibility antigen, DP(W2) beta chain is a protein that in humans is encoded by the ''HLA-DPB1'' gene.
HLA-DPB belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha ( ...
. Most of the HLA alleles currently present in the human population can be explained by gene conversion between these ancient ancestral types,
some that persist into the extant population.
Serogroups
The table below provides links to subpages with information about distribution, genetic
linkage and disease association for the HLA-DR serogroups.
Interlocus DRB linkage
DRB1 is linked with other DRB loci in four ways.
References
Further reading
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External links
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{{DEFAULTSORT:Hla-Dr
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Genes on human chromosome 6
MHC class II