Human Leukocyte Antigen (HLA)
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Human Leukocyte Antigens (HLA) consists of a family of genes within the major histocompatibility complex (MHC) on the short arm of chromosome 6 in humans. It contains over 200 genes, over 40 of which encode leukocyte proteins that distinguish self from non-self antigens. There are two major classes of genes, I and II, involved in the immune response, which are both structurally and functionally different. Class I genes code for the a-polypeptide chain of class I molecules while the class I β-chain is encoded by the β2-microglobulin gene on chromosome 15. This is in contrast to class II genes which code for both class II α and β-chains.
HLA class I genes, particularly HLA A, B, and C, are expressed by most nucleated cells and are essential to target infected cells for killing by CD8+ cytotoxic T lymphocytes. CTLs require the presentation of foreign antigen by the HLA class I peptides for activation of immune response. Natural killer cell attack of infected or tumor cells which is critical to the innate immune response, also requires the absence of self-HLA class I genes.
On the other hand, HLA Class II peptides, encoded particularly by DQ, DR, and DP a andβgenes, are only found on the surface of “professional” antigen presenting cells, such as macrophages or lymphocytes. These cells present antigenic peptide in conjunction with Class II antigens to CD4+ T helper cells for proper immune recognition.
The primary purpose of these molecules is to bind and present "foreign" peptides, originating from viruses, bacteria or other immunogens, to the host immune system and stimulate an immune reaction from other cells. Within the field of transplantation, mismatched HLA typing between the donor and recipient presents a problem since the host immune system will recognize the mismatched donor HLA as "foreign" and mount a combined cellular and humoral immune response against the mismatched donor HLA.
HLA loci are highly polymorphic and the encoded genes result in products that differ in the peptide-binding cleft which influence specificity to the foreign antigens bound and presented to T cells. While alleles are all alternative forms of a gene at a given locus including rare mutant alleles, a polymorphism is specifically defined as the occurrence of two or more alleles or sequence variations at the same genetic locus in a population at such a frequency that the rarest could not be maintained by recurrent mutation alone.
Antibodies specific for Human Leukocyte Antigen (HLAAb), and the humoral theory of transplantation, have gained recognition as the primary cause of chronic allograft rejection. HLA antibodies pose a problem for allograft survival in both the pre-transplant and post-transplant scenarios. In the pre-transplant period, transplant surgeons and tissue typing laboratories must assure that donor and patient are HLA matched to avert de novo HLA antibody formation. In addition, if pre-formed HLA antibodies are specific to donor HLA, the antibodies would immediately begin to destroy the allograft upon transplantation and result in hyperacute rejection. To test for donor-specific HLA antibody reactivity pre-transplant, a flow or cytotoxicity-dependent-cell (CDC) crossmatch is performed by mixing patient serum (containing HLA antibodies) and donor lymphocytes together. If either the CDC or flow crossmatch is positive, the patient is typically placed back on the waiting list until a more suitable donor can be found.
Class I MHC molecules display a broad polymorphism which affects peptide uptake, the variation of peptides, and their ability to be recognized by immune cells. A high degree of polymorphism gives the classic MHC molecules a greater ability to present a wide range of antigenic peptides for recognition by T-lymphocytes. In contrast, non-classical HLA-G, presents very low polymorphism making it unsuitable for peptide binding and antigen presentation. Instead, due to the unique molecular structure and the three α-domains HLA-G has a high affinity for inhibitory receptors located on immune cells.
Human Leukocyte Antigen-G (HLA-G) belongs to MHC class I molecules, however, its functions make it different from the regular molecules in this category, as HLA-G induces immune suppression rather than immune activation. Its role has been initially studied in the context of pregnancy where it has been found to facilitate a tolerogenic environment for the allogeneic fetus. HLA-G is known to protect the fetus from the maternal immune system by exerting a series of inhibitory functions altering the immune cells’ allorecognition and attack. HLA-G has a restricted healthy tissue expression and it is also found in thymic epithelial cells, pancreatic islets, cornea, erythroblasts, and mesenchymal cells. HLA-G is up-regulated in pathological conditions such as cancer, autoimmune and inflammatory diseases, viral infections and transplantation.
Unlike classical MHC, HLA-G has a limited polymorphism, a limited tissue expression, immune suppressive properties, limited protein variability, and distinctive molecular structure with a reduced cytoplasmatic tail. Although the genetic structure of HLA-G is similar to other MHC antigens, its primary transcript produces seven isoforms generated through alternative splicing of the same mRNA: four membrane-bound (HLA-G1, -G2, -G3, and -G4) and three soluble ones (HLA-G5, -G6, and -G7). The HLA-G transcripts produced can be expressed in various cell types or in different pathologic or non-pathologic situations.
The importance of the MHC class II (MHCII) pathway is highlighted by its role in disease. The lack of MHCII expression in bare lymphocyte syndrome results in severe combined immunodeficiency with significant deficiencies both in cellular and humoral immunity. Susceptibility to many autoimmune diseases have been localized directly to the MHCII locus with susceptibility to multiple sclerosis and rheumatoid arthritis being linked to specific HLA-DRB1 alleles. In addition many viral homologues have been identified that target the MHCII presentation pathway either by blocking interferon γ (IFNγ) induced MHC class II transactivator (CIITA) expression or by interfering with MHCII protein stability and trafficking. For example poxviruses produce soluble IFNγ receptor homologues that compete for IFNγ binding with the host's own surface receptors. In the case of targeting protein stability, the human cytomegalovirus glycoprotein US2 has been shown to target both the HLA-DM (DM) and HLA-DR (DR) a chains for retro-translocation from the endoplasmic reticulum (ER) into the cytosol and subsequent degradation by the proteasome in a similar fashion as it targets MHC class I (MHCI) heavy chain. Some viruses also have been shown to induce interleukin-10 (IL-10) expression or to express a viral homologue of IL-10, which leads to a pH increase in MHC class II compartments (MIIC) and affects trafficking of MHCII molecules to and from the cell surface. Gp42 expressed by Epstein-Barr virus has a dual effect in the MHCII pathway. First it is crucial for entry of virions into the cell through binding surface MHCII molecules. Once cells are infected, gp42 is secreted in a soluble form and prevents CD4+ T cell interaction by binding to MHCII. Furthermore, the herpes simplex virus 1 protein gB binds to DR and thereby hinders it from interacting with invariant chain (Ii). MHCII is also targeted by bacterial superantigens to manipulate CD4+ T cell responses and by viral superantigens to enhance the growth rate of the infected cell through recruitment of T cell help. Targeting of the MHCII pathway by pathogens and the dramatic phenotype caused by deficiency of MHCII molecules emphasizes the importance of MHCII antigen presentation.
HLA related literatures
1. Klein J A N, Sato A. The HLA system: first of two parts[J]. The New England journal of medicine, 2000, 343(10): 702-709.
2. Koopman L A, Corver W E, Van Der Slik A R, et al. Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer[J]. The Journal of experimental medicine, 2000, 191(6): 961-976.
3. Reith W, Mach B. The bare lymphocyte syndrome and the regulation of MHC expression[J]. Annual review of immunology, 2001, 19(1): 331-373.
4. Rouas-Freiss N, Marchal R E, Kirszenbaum M, et al. The α1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors?[J]. Proceedings of the National Academy of Sciences, 1997, 94(10): 5249-5254.
