Available structural: , , , , , , ,
|Mass / length primary structure||38 kilodaltons / 338 amino acids|
|Gene name (s)||HLA-G HLA-6.0, HLAG|
HLA-G is an immunoregulatory protein from the HLA-Ib family, i.e. from the family of non-classical human leukocyte antigens of class I. Its main function is immunomodulation , especially during pregnancy, in which there are natural killer cells and cytotoxic T- Prevents cells from attacking the tissue of the fetus by binding to inhibitory (i.e. activity-inhibiting) receptors .
Gene and protein
The gene for HLA-G is - like the other HLA genes - in the main histocompatibility complex (MHC) on the short arm of chromosome 6 . In contrast to the extremely polymorphic classical human leukocyte antigens of the HLA-Ia family (HLA-A and HLA-B), its polymorphism is limited, ie there are only a few alleles (so-called oligomorphism). There are seven isoforms , including four with a transmembrane domain , which are therefore membrane-bound (HLA-G1 to HLA-G4), and three soluble ones that lack this domain (HLA-G5, HLA-G6 and HLA-G7). Membrane-bound isoforms can also become soluble proteins if metalloproteases cleave the transmembrane domains. The finished protein consists of an α-subunit with three α-domains and possibly a transmembrane domain as well as an attached β2-microglobulin . Some of the isoforms can assemble into dimers .
While almost all body cells express HLA-Ia molecules, the expression of HLA-G is strictly limited. The gene is read, especially during pregnancy, in trophoblast cells , which are located in the placenta at the border between fetal and maternal tissue. HLA-G also contributes to immune modulation in other so-called immune-privileged locations where defense reactions have to be inhibited so that an organ or tissue can function properly - for example in the cornea and in the nail matrix . The cells of the thymus and pancreas , monocytes and the progenitor cells of erythrocytes and endothelial cells also express HLA-G.
Under pathological conditions, HLA-G is also expressed elsewhere, in particular in virus-infected cells or in tumors . HLA-G production is also increased in chronically inflamed tissue, for example in the cerebrospinal fluid of many patients with multiple sclerosis . After a transplant , HLA-G can also be expressed locally, which dampens the rejection reaction.
Even the small number of alleles indicates a fundamentally different mechanism of action than that of classic HLA molecules: While the highly polymorphic HLA-A and HLA-B molecules bind countless different antigens and they cause the cytotoxic T on the surface of almost all cell types Cells present, HLA-G does not bind antigens. Rather, both the membrane-bound and the soluble forms bind directly to at least four specific inhibitory receptors on different cells of the immune system. They inhibit the activity of natural killer cells (NK cells), cytotoxic T cells, B cells and other antigen presenting cells such as macrophages .
Immune modulation occurs in several ways. For example, cytotoxic T cells and natural killer cells are inactivated and stimulated to apoptosis , i.e. programmed cell death, CD4 + T cells are prevented from multiplying and B cells are prevented from maturing. By inhibiting the formation and activation of inflammation-promoting type 1 T helper cells , the immune system is polarized in the direction of type 2 T helper cells. HLA-G also stimulates the formation of immune tolerance-promoting regulatory T cells and dendritic cells , which secrete the anti-inflammatory interleukin IL-10. Since IL-10 in turn promotes the expression of HLA-G, there can be a positive feedback that stabilizes the anti-inflammatory process.
Function under physiological conditions
During pregnancy, the so-called cytotrophoblast (part of the trophoblast ) produces HLA-G, which binds to inhibitory receptors on various maternal immune cells in the placenta, mainly natural killer cells, and thus prevents the destruction of fetal tissue. This would otherwise be attacked by the maternal immune system as semi-allogeneic tissue because of its half paternal genes. In addition, the HLA-G stimulates the remodeling and expansion of the blood vessel network in the uterus, which is necessary to supply the fetus with nutrients. HLA-G is supported by HLA-E and HLA-F, two other, less well-researched proteins of the HLA-Ib family.
Function under pathological conditions
Many tumors disguise themselves to a certain extent as fetuses by expressing HLA-G and are consequently not attacked by the immune system, although their other surface markers identify them as dangerous. Viruses can also start HLA-G expression in their host cells so that the infected cells are not destroyed by the immune system.
In the case of some chronic inflammations and autoimmune diseases , either more or less soluble HLA-G can be detected in the blood of those affected than in healthy people. Certain gene variants are possible causes. For example, in one variant, a 14 base pair sequence is inserted at one end of the gene, which is missing in the other variant. The sequence influences the stability of the messenger RNA , which is read from the DNA, and thus the amount of newly produced HLA-G.
In lupus erythematosus, for example, the longer allele is more common than in the general population, and patients who inherited this variant from both parents have more severe symptoms than those who inherited the shorter allele from one parent. However, the mere detection of HLA-G in a diseased tissue is not yet evidence of a contributory cause of the disease. Especially in those autoimmune diseases that are characterized by autoreactive type 1 T helper cells, HLA-G expression can also serve to reduce chronic inflammation by inhibiting the type 1 T helper cells and polarizing them in the direction of the type To dampen 2 helper cells. This applies to type 1 diabetes and multiple sclerosis , for example .
- ED Carosella, N. Rouas-Freiss: How the unborn child protects itself from the mother . In: Spektrum der Wissenschaft , June 2012 pp. 22–29
- G. Curigliano et al. a .: Molecular Pathways: Human Leukocyte Antigen G (HLA-G) In: Clinical Cancer Research , October 2013, doi : 10.1158 / 1078-0432.CCR-12-3697
- F. Morandi, V. Pistoia: Interactions between HLA-G and HLA-E in physiological and pathological conditions . In: Frontiers in Immunology , August 2014, 5: 394, doi : 10.3389 / fimmu.2014.00394 (Mini Review)
- R. Rizzo et al. a .: HLA-G molecules in autoimmune diseases and infections . In: Frontiers in Immunology , November 2014, 5: 592, doi : 10.3389 / fimmu.2014.00592 (Review)