Histocompatibility Antigens

Definition
Histocompatibility molecules are glycoproteins expressed at the surface of almost all vertebrate cells. They get their name because they are responsible for the compatibility or rather the lack of it — of the tissues of genetically different individuals. Monozygotic ("identical") human twins have the same histocompatibility molecules on their cells, and they can accept transplants of tissue from each other. So the histocompatibility molecules of one individual act as antigens when introduced into a different individual. In fact, the histocompatibility molecules are often called histocompatibility antigens or transplantation antigens.

Structural Characteristics
Located in the short arm of chromosome 6, HLA is composed of more than 200 genes, of which about 20% codify histocompatibility molecules expressed on the cell surface.2 These genes, which take part in the immunologic response, are didactically divided into three classes: I, II and III, being different between themselves as to structure and function.3 Class I region has three main loci: HLA-A, HLA-B and HLA-C, whereas class II HLA contains the HLA-DR, HLA-DQ and HLA-DP loci. Class I and II HLA genes codify classical histocompatibility molecules. Class III HLA genes codify complement factors, tumor necrosis factor and 21-hydroxylase enzyme, among others.

Structure of crossreactive human histocompatibility antigens HLAA28 and HLA-A2: Possible implications for the generation of HLA polymorphism - The primary structure of two highly crossreactive human histocompatibility antigen, HLA-A28 and HLA-A2, has been determined to 96% and 90%, respectively, of the papain solubilized molecules. Their sequences have been compared with the sequence of HLA-B7 and with each other in order to outline the sites of diversity. The overall homology between HLA-B7 and these HLA-A antigens is 86%. A large majority of the differences are located between residues 43 and 195. Within this area, substitutions cluster in at least three segments-residues 65-80, 105-116, and 177-194. HLA-A28 and HLA-A2 show 96% homology. Most of the differences fall within segments 65-74 and 107-116. it has been shown that residues in these segments are integral parts of the alloantigenic determinants of HLA-A28 and HLA-A2. It is further proposed that these three clusters may constitute major, albeit not exclusive, sites of antigenic diversity in human histocompatibility antigens. The nature of the differences among HLA-B7, HLA-A28, and HLA-A2 in the first variable segment suggests that gene conversion might play some role in the generation of HIA polymorphism1.

Mode of Action
The role of HLA Class I molecules is to take these virally induced peptides to the surface of the cell and by linking to the T-Cell receptor of a Cytotoxic (CD8) T Cell, demonstrate the presence of this virus. The CD8T Cell will now be “educated” and it will be able to initiate the process of killing cells which subsequently has that same viral protein/HLA Class I molecule on its surface2, 3. The expression of HLA Class II, on cells, which would not normally express them, is stimulated by cytokines like interferon g and in a transplant, this is associated with acute graft destruction.HLA Class II molecules consist of two chains each encoded by genes in the “HLA Complex” on Chromosome 6. The T Cells, which link up to the HLA Class II molecules, are Helper (CD4) T cells. Thus the “education” process which occurs from HLA Class II presentation, involves the helper-function of setting up a general immune reaction which will involve cytokines, cellular and humoral defense against the bacterial (or other) invasion2, 3.

Functions
Associoation of HLA with Lupus erythematosus - Lupus erythematosus is an autoimmune disorder with a wide spectrum of clinical manifestations ranging from the cutaneous forms (CLE) to the multisystemic disease. Experimental studies suggest a strong association with polymorphic genes codifying immunoregulatory molecules (e.g., HLA, TNF-a complement), especially in patients anti-Ro-positive. HLA-B8 and –DR3 antigens were associated with the development of SCLE. In some studies, HLA-DR3 antigen was detected in more than 50% of patients with SCLE4.

Influence of human histocompatibility antigens on susceptibility to and clinical expression of psychiatric diseases (Bipolar disorder) - The antigen HLA-B16 has been generally associated with mood disorders, including maniac and purely depressive disorders. The antigens HLA-A10, HLA-A29, HLA-B7, HLA-B16 and HLA-B21 have been more frequently found in patients with bipolar disorder, compared with healthy controls5. Lithium is a mood-stabilizing agent often used for the treatment of bipolar disorder. Some researches have suggested that, as other chemotherapy agents, this drug may change the expression of HLA molecules. The two main HLA classes seem to be affected differently by the drug; changes in class II HLA are more significant from the functional perspective. Reduction and loss of expression of class I histocompatibility molecules on the cell surface have been reported, whereas changes in class II HLA have occurred at the genomic DNA level. It is still unknown how lithium is able to cause these changes, which may be present 2 weeks after taking the drug in usual therapeutic doses6.

References
1.López de Castro JA, Strominger JL, Strong DM, Orr HT (1982). Structure of crossreactive human histocompatibility antigens HLAA28 and HLA-A2: Possible implications for the generation of HLA polymorphism. Proc. Natl. Acad. Sci, 79:3813-3817.
2.Shankarkumar U, Ghosh K, Mohanty D (2002). The Human Leukocyte Antigen (HLA) System. J Assoc Physicians, 50:916-926.
3.Book: HLA and MHC: Genes, Molecules and Function. By Browning M, Mc Michael
4.Provost TT, Watson R (1993). Anti-Ro (SS-A) HLA-DR3-positive women: the interrelationship between some ANA negative, SS, SCLE, and NLE mothers and SS/LE overlap female patients. J. Invest. Dermatol, 100: 14-20.
5.Ucok A, Akar U, Polat A, Yazici O (2005). Human leukocyte antigen alleles in patients with bipolar disorder in Turkey. Eur. Psychiatry., 20(1):83.
6.Kang BJ, Park SW, Chung TH (2000). Can the expression of histocompatibility antigen be changed by lithium?. Bipolar. Disord, 2(2):140-144.