HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''HLA-G''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
HLA-G belongs to the
HLA nonclassical class I heavy chain paralogues. Classical HLA I proteins are found on all nucleated cells and express
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
s in their peptide binding groove. They can express "self" peptides when the cell is healthy as well as foreign peptides when the cell is infected by a parasite or cancer. HLA-G is a nonclassical protein and serves a different function from classical HLA class I molecules, but it still expresses a nine amino acid peptide in its peptide binding groove.
The third and ninth amino acid in the peptide sequence serve as anchor residues, and are thus conserved in all the peptides HLA-G bind to.
Structure
This class I molecule is a heterodimer consisting of a heavy chain and a light chain (
beta-2 microglobulin
β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells (excluding red blood cells). In humans, the β2 microglobulin protein is encoded by th ...
). The heavy chain is anchored in the membrane. HLA-G is coded for by 88 alleles.
The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail.
Exon 7 and 8 are not translated due to a stop codon present in exon 6.
HLA-G can be expressed under at least seven isoforms through alternative splicing, called HLA-G1, HLA-G2,..., HLA-G7.
The proterin can be both membrane-bound and soluble. HLA-G1 through G4 are membrane bound and HLA-G5 through G7 are soluble.
HLA-G1 and HLA-G5 are the most studied isoforms due to the wider availability of antibodies targeting them. HLA-G can present a more narrow variety of peptides than its classical HLA class I counterparts due to it having a more limited polymorphism.
Function
In the Human Body
HLA-G is a major immune checkpoint, meaning it downregulates the immune system's response.
Soluble HLA-G can be found in the saliva, ascitic fluid, plasma, thymus, seminal plasma, cerebrospinal fluid, and in first and second term placentas.
Membrane-bound HLA-G is predominantly found on trophoblast cells in the placenta, but it is also found in the thymus, cornea, erythroblasts, and mesenchymal stem cells.
It can be upregulated in cancers.
Peptides are connected to HLA-G by the peptide loading complex in the endoplasmic reticulum.
Pregnancy
HLA-G plays a role in
immune tolerance in pregnancy Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign i ...
, being expressed in the
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
by extravillous trophoblast cells (EVT), while the classical
MHC class I genes (
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 ...
and
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 ...
) are not.
As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss.
Its downregulation is related to HLA-A and -B downregulation results in protection from
cytotoxic T cell responses, but would in theory result in a ''missing self'' response by
natural killer cells. HLA-G is a ligand for natural killer (NK) cell inhibitory receptor
KIR2DL4
Killer cell immunoglobulin-like receptor 2DL4 is a protein that in humans is encoded by the ''KIR2DL4'' gene.
Function
Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and sub ...
, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death.
However, a large family with several members bearing only "null" HLA-G alleles has been found. None of these homozygous subjects have pregnancy or birth difficulties; nor do they present immunodeficiencies, autoimmune diseases, or tumors.
It is striking that this "null" allele (HLA-G*01:05N), while it is quite frequent in some populations, like in Iranians, it is almost absent in some Amerindian populations.
Also, some higher primates do not show all MHC-G isoforms.
In addition, Cercopithecinae middle-sized Old World monkeys do not bear full MHC-G molecules since all of these monkeys present stop codons at MHC-G DNA.
All of these anomalies must be studied.
The presence of soluble HLA-G (sHLA-G) in embryos is associated with better
pregnancy rate Pregnancy rate is the success rate for getting pregnancy, pregnant. It is the percentage of all attempts that leads to pregnancy, with attempts generally referring to menstrual cycles where insemination or any artificial equivalent is used, which ma ...
s. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos.
However, presence of soluble HLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.
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Parasitic Infections
HLA-G has been shown to modulate the body's response to parasitic diseases. Recent studies have emerged suggesting a link between HLA-G and '' P. falciparum'', which is one of the most dangerous malaria strains. In pregnant women, ''P. falciparum'' can infect the placenta, causing low birth weights and other complications. High levels of soluble HLA-G have been linked to higher instances of low birth weights. There is also a link between HLA-G expression and Human African trypanosomiasis (HAT). People with higher levels of soluble HLA-G are more likely to be diagnosed with the disease. There may also be genetic differences driving the instance and severity of HAT, as a few single nucleotide polymorphisms have been associated with higher levels of HAT. There is also an effect in Toxoplasmosis
Toxoplasmosis is a parasitic disease caused by '' Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or mont ...
infections in pregnant women, where HLA-G is upregulated to protect the fetus from inflammation. Treatment of cells with IL-10 leads to a downregulation of HLA-G, which could be an avenue for therapy in instances where too much HLA-G is produced. Individuals with Visceral leishmaniasis
Visceral leishmaniasis (VL), also known as kala-azar (Hindi: kālā āzār, "black sickness") or "black fever", is the most severe form of leishmaniasis and, without proper diagnosis and treatment, is associated with high fatality. Leishmaniasi ...
infections also have higher levels of soluble HLA-G, which may be due to a strategy by Leishmania to evade the immune system.
Cancer
HLA has been shown to be associated with tumor escape in cancers, because it causes the immune system to not pay attention to cancer cells. Because it is upregulated in cancer cells, it could serve as a potential target for immunotherapy. Monoclonal antibodies that bind to HLA-G have been used successfully against cancers as part of a strategy to inhibit immune checkpoints. HLA-G has potential utility as a tumor marker due to the large increase in HLA-G in many cancers, including breast cancer, ovarian cancer, and lung cancer.
Allergy
HLA-G has links to allergenic responses in the body. Soluble HLA-G levels are higher in the serum of people with allergic rhinitis
Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, i ...
, or hay fever. Additionally, single nucleotide polymorphisms in HLA-G have been connected to an increased likelihood of having asthma. Papillary cells expressing HLA-G were found in patients with atopic dermatitis.
Interactions
HLA-G has been shown to interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with CD8A. When in its soluble form, HLA-G interacts with Ig-like transcript 2 (ILT2), a leukocyte receptor. When it’s membrane bound, it interacts with Ig-like transcript 4 (ILT4). Soluble HLA-G can bind to KIR2DL4, which is often found on the surface of natural killer cells. The identity of the peptide presented by HLA-G is unrelated to the binding of HLA with KIR2DL4, ILT2, or ILT4. Because HLA-G interacts with receptors using a variety of its domains, multiple antibodies are necessary to inhibit all of its functions.
Both ILT2 and ILT4 cause negative intracellular signaling. In monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s, binding to either ILT2 or ILT4 receptors cause the inhibition of monocyte/ macrophage mediated toxicity. In dendritic cells, binding to both receptors can prevent dendritic cells from maturing and prevent the activation of T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s. Additionally, HLA-G may interact with ILT4 receptors on the surface of neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s to inhibit phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
. In natural killer cells, HLA-G binds with the ILT2 receptor to inhibit the secretion of IFN-γ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
, a cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
that can activate macrophages and stimulate natural killer cells and neutrophils. HLA-G binds to ILT2 on B cells to cause the inhibition of B cell proliferation, differentiation, and the secretion of antibodies. It binds to ILT2 on T cells to downregulate T cell chemokine expression. The cytokine expression of T cells mimics that of TH2 cells. HLA-G causes apoptosis in CD8+ T cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
. All together these effects serve to decrease the inflammatory response of the immune system.
References
Further reading
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{{Surface antigens