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 ex
Unlike classical MHC, HLA-G has a limited polymorphism, a limited tissue ex
The importance of the MHC class II (MHCII) pathway is highlighted by its role in disease. The lack of MHCII ex
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 ex
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.