HLA-G

Last updated
HLA-G
Protein HLA-G PDB 1ydp.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HLA-G , MHC-G, major histocompatibility complex, class I, G
External IDs OMIM: 142871 MGI: 95915 HomoloGene: 133255 GeneCards: HLA-G
Orthologs
SpeciesHumanMouse
Entrez

3135

14991

Ensembl

ENSMUSG00000016206

UniProt

P17693

Q31093

RefSeq (mRNA)

NM_002127
NM_001363567
NM_001384280
NM_001384290

NM_013819

RefSeq (protein)

NP_002118
NP_001350496

NP_038847

Location (UCSC) Chr 6: 29.83 – 29.83 Mb Chr 17: 37.58 – 37.59 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene. [5]

Contents

HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. Classical HLA I proteins are found on all nucleated cells and express peptides 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. [6] 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). The heavy chain is anchored in the membrane. HLA-G is coded for by 88 alleles. [7] 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. [5] Exon 7 and 8 are not translated due to a stop codon present in exon 6. [8]

HLA-G can be expressed under at least seven isoforms through alternative splicing, called HLA-G1, HLA-G2,..., HLA-G7. [6] [9] The protein can be both membrane-bound and soluble. HLA-G1 through G4 are membrane bound and HLA-G5 through G7 are soluble. [6] 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. [9] Soluble HLA-G can be found in the saliva, ascitic fluid, plasma, thymus, seminal plasma, cerebrospinal fluid, and in first and second term placentas. [10] 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. [7] It can be upregulated in cancers. [9] Peptides are connected to HLA-G by the peptide loading complex in the endoplasmic reticulum. [6]

Pregnancy

HLA-G plays a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells (EVT), while the classical MHC class I genes (HLA-A and HLA-B) are not. [6] [11] 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. [12] 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, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death. [13]

The presence of soluble HLA-G (sHLA-G) in embryos is associated with better pregnancy rates. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos. [14] 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. [14]

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. [7] 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). [7] 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 infections in pregnant women, where HLA-G is upregulated to protect the fetus from inflammation. [7] 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 infections also have higher levels of soluble HLA-G, which may be due to a strategy by Leishmania to evade the immune system. [7]

Cancer

HLA-G 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. [9] Monoclonal antibodies that bind to HLA-G have been used successfully against cancers as part of a strategy to inhibit immune checkpoints. [6] 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. [10] Increased expression of HLA-G has been associated with the metastatic potential of tumor cells. [15]

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, or hay fever. [16] 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. [16]

Interactions

HLA-G has been shown to interact with CD8A. [17] [18] 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). [6] [7] 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. [6] 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. [7] In monocytes, 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 cells. [7] Additionally, HLA-G may interact with ILT4 receptors on the surface of neutrophils to inhibit phagocytosis. In natural killer cells, HLA-G binds with the ILT2 receptor to inhibit the secretion of IFN-γ, a cytokine that can activate macrophages and stimulate natural killer cells and neutrophils. [7] 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. [6] All together these effects serve to decrease the inflammatory response of the immune system.

Related Research Articles

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Most immune cells detect the antigen presented on major histocompatibility complex (MHC) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">Human leukocyte antigen</span> Genes on human chromosome 6

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 regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens, or from phagocytosed pathogens ; subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway.

<span class="mw-page-title-main">HLA-DR</span> Subclass of HLA-D antigens that consist of alpha and beta chains

HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA were originally defined as cell surface antigens that mediate graft-versus-host disease. Identification of these antigens has led to greater success and longevity in organ transplant.

<span class="mw-page-title-main">MHC class II</span> Protein of the immune system

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, and B cells. These cells are important in initiating immune responses.

<span class="mw-page-title-main">HLA-A</span> Protein-coding gene in the species Homo sapiens

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 human MHC class I transmembrane proteins. The others are HLA-B and HLA-C. The protein is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is encoded by the B2M gene, which is located at chromosome 15q21.1 in humans.

<span class="mw-page-title-main">HLA-C</span> Protein-coding gene in the species Homo sapiens

HLA-C belongs to the MHC class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane. MHC Class I molecules, like HLA-C, are expressed in nearly all cells, and present small peptides to the immune system which surveys for non-self peptides.

<span class="mw-page-title-main">HLA-E</span> Protein-coding gene in the species Homo sapiens

HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene. The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called Qa-1b, officially known as H2-T23.

<span class="mw-page-title-main">KLRD1</span>

CD94, also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human gene.

<span class="mw-page-title-main">HLA-DRB4</span> Protein-coding gene in the species Homo sapiens

Major histocompatibility complex, class II, DR beta 4, also known as HLA-DRB4, is a human gene.

<span class="mw-page-title-main">CD74</span> Mammalian protein found in Homo sapiens

HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74, is a protein that in humans is encoded by the CD74 gene. The invariant chain is a polypeptide which plays a critical role in antigen presentation. It is involved in the formation and transport of MHC class II peptide complexes for the generation of CD4+ T cell responses. The cell surface form of the invariant chain is known as CD74. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF).

<span class="mw-page-title-main">LILRB1</span> Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 1 is a protein that in humans is encoded by the LILRB1 gene.

<span class="mw-page-title-main">CD69</span>

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

<span class="mw-page-title-main">HLA-DRB3</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DRB3-1 beta chain is a protein that in humans is encoded by the HLA-DRB3 gene.

<span class="mw-page-title-main">HLA-F</span> Protein-coding gene in the species Homo sapiens

HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene. It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include IFN-gamma signaling and CDK-mediated phosphorylation and removal of the Saccharomycescerevisiae Cdc6 protein, which is crucial for functional DNA replication.

<span class="mw-page-title-main">HLA-DMB</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DM beta chain is a protein that in humans is encoded by the HLA-DMB gene.

<span class="mw-page-title-main">LILRB2</span> Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 2 is a protein that in humans is encoded by the LILRB2 gene.

<span class="mw-page-title-main">HLA-DOB</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DO beta chain is a protein that in humans is encoded by the HLA-DOB gene.

Immunoediting is a dynamic process that consists of immunosurveillance and tumor progression. It describes the relation between the tumor cells and the immune system. It is made up of three phases: elimination, equilibrium, and escape.

References

  1. 1 2 3 ENSG00000233095, ENSG00000237216, ENSG00000276051, ENSG00000204632, ENSG00000235346, ENSG00000235680, ENSG00000206506 GRCh38: Ensembl release 89: ENSG00000230413, ENSG00000233095, ENSG00000237216, ENSG00000276051, ENSG00000204632, ENSG00000235346, ENSG00000235680, ENSG00000206506 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000016206 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: HLA-G HLA-G histocompatibility antigen, class I, G".
  6. 1 2 3 4 5 6 7 8 9 Attia JV, Dessens CE, van de Water R, Houvast RD, Kuppen PJ, Krijgsman D (November 2020). "The Molecular and Functional Characteristics of HLA-G and the Interaction with Its Receptors: Where to Intervene for Cancer Immunotherapy?". International Journal of Molecular Sciences. 21 (22): 8678. doi: 10.3390/ijms21228678 . PMC   7698525 . PMID   33213057.
  7. 1 2 3 4 5 6 7 8 9 10 Zhuang B, Shang J, Yao Y (2021). "HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance". Frontiers in Immunology. 12: 744324. doi: 10.3389/fimmu.2021.744324 . PMC   8586502 . PMID   34777357.
  8. ↑ Castelli EC, Mendes-Junior CT, Veiga-Castelli LC, Roger M, Moreau P, Donadi EA (November 2011). "A comprehensive study of polymorphic sites along the HLA-G gene: implication for gene regulation and evolution". Molecular Biology and Evolution. 28 (11): 3069–3086. doi: 10.1093/molbev/msr138 . PMID   21622995.
  9. 1 2 3 4 Loustau M, Anna F, Dréan R, Lecomte M, Langlade-Demoyen P, Caumartin J (2020). "HLA-G Neo-Expression on Tumors". Frontiers in Immunology. 11: 1685. doi: 10.3389/fimmu.2020.01685 . PMC   7456902 . PMID   32922387.
  10. 1 2 Li P, Wang N, Zhang Y, Wang C, Du L (2021). "HLA-G/sHLA-G and HLA-G-Bearing Extracellular Vesicles in Cancers: Potential Role as Biomarkers". Frontiers in Immunology. 12: 791535. doi: 10.3389/fimmu.2021.791535 . PMC   8636042 . PMID   34868081.
  11. ↑ Jay Iams; Creasy, Robert K.; Resnik, Robert; Robert Reznik (2004). Maternal-fetal medicine. Philadelphia: W.B. Saunders Co. pp.  31–32. ISBN   978-0-7216-0004-8.
  12. ↑ Michita RT, Zambra FM, Fraga LR, Sanseverino MT, Callegari-Jacques SM, Vianna P, Chies JA (October 2016). "A tug-of-war between tolerance and rejection - New evidence for 3'UTR HLA-G haplotypes influence in recurrent pregnancy loss". Human Immunology. 77 (10): 892–897. doi:10.1016/j.humimm.2016.07.004. PMID   27397898.
  13. ↑ Lash GE, Robson SC, Bulmer JN (March 2010). "Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua". Placenta. 31 (Suppl): S87–S92. doi:10.1016/j.placenta.2009.12.022. PMID   20061017.
  14. 1 2 Rebmann V, Switala M, Eue I, Grosse-Wilde H (July 2010). "Soluble HLA-G is an independent factor for the prediction of pregnancy outcome after ART: a German multi-centre study". Human Reproduction. 25 (7): 1691–1698. doi: 10.1093/humrep/deq120 . PMID   20488801.
  15. ↑ Bassey-Archibong BI, Rajendra Chokshi C, Aghaei N, Kieliszek AM, Tatari N, McKenna D, et al. (February 2023). "An HLA-G/SPAG9/STAT3 axis promotes brain metastases". Proceedings of the National Academy of Sciences of the United States of America. 120 (8): e2205247120. Bibcode:2023PNAS..12005247B. doi:10.1073/pnas.2205247120. PMC   9974476 . PMID   36780531.
  16. 1 2 Negrini S, Contini P, Murdaca G, Puppo F (2022). "HLA-G in Allergy: Does It Play an Immunoregulatory Role?". Frontiers in Immunology. 12: 789684. doi: 10.3389/fimmu.2021.789684 . PMC   8784385 . PMID   35082780.
  17. ↑ Gao GF, Willcox BE, Wyer JR, Boulter JM, O'Callaghan CA, Maenaka K, et al. (May 2000). "Classical and nonclassical class I major histocompatibility complex molecules exhibit subtle conformational differences that affect binding to CD8alphaalpha". The Journal of Biological Chemistry. 275 (20): 15232–15238. doi: 10.1074/jbc.275.20.15232 . PMID   10809759.
  18. ↑ Sanders SK, Giblin PA, Kavathas P (September 1991). "Cell-cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class 1 molecule on cytotrophoblasts". The Journal of Experimental Medicine. 174 (3): 737–740. doi:10.1084/jem.174.3.737. PMC   2118947 . PMID   1908512.

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