La région HLA de classe I du CMH : une des régions les plus complexes du génome humain ?

Abstract

Le complexe majeur d’histocompatibilité (CMH) est un segment génomique situé sur le chromosome 6 comportant un nombre considérable de gènes impliqués dans la fonction immunitaire dont la carte commence à être relativement détaillée. Les gènes HLA de classe I occupent environ 2 000 kb dans la moitié télomérique du CMH. Trois gènes extrêmement polymorphes codent pour les antigènes leucocytaires classiques HLA-A, HLA-B et HLA-C, glycoprotéines ancrées à la surface des cellules qui, d’une part, présentent aux récepteurs des lymphocytes T les peptides antigéniques issus de protéines endogènes et, d’autre part, sont reconnues par les récepteurs des cellules natural killer ; trois gènes, HLA-E, HLA-F et HLA-G, à la structure très proche, ont une fonction biologique encore incertaine. Outre ces six gènes, le CMH contient de nombreux pseudogènes de classe I et des fragments de gènes issus d’un gène ancestral HLA de classe I, mais aussi d’autres gènes, copies uniques ou familles multigéniques, tout cela formant une région dont la densité génique est extrêmement élevée.

The human major histocompatibility complex (MHC) is a 4-Mb genomic segment located on chromosome 6, in the distal portion of the 6p21.3 band. The MHC is a well described region of the human genome and represents a cluster of genes intensively studied because of the important functions of the gene products in the immune system. The total number of genes located within the MHC is now approximately 100, but more can be predicted. The density of genes in the Class II and Class III regions has been known for several years, but the high density of genes in the Class I region did only recently become apparent. This class I region spans 2,000 kb on the telomeric half of the MHC, and contains six class I genes, three of which, the classical human leukocyte antigen genes HLA-A, HLA-B and HLA-C, encode membrane-anchored cell surface glycoproteins that present the endogenous antigenic peptides to the T cell receptors and are recognized by NK cell receptors. These genes are characterized by a high polymorphism and a nearly ubiquitous expression. The biological function of the three nonclassical class I genes HLA-E, HLA-F, and HLA-G still remains uncertain. In addition to these six genes, the MHC contains a number of class I pseudoaenes and gene fragments whose close relationship indicates a common origin from a typical HLA class I ancestor gene. This region appears also to harbour various non-HLA single copy genes such as OTF3, TCF19, S gene, TUBB, HSR1, B30.2, ZNF173, HCG V, HCG-VII, MOG or OLFR2 as well as eight recently described multigene families named P5.1, 3.8-1, PERB11, BAT1, HCGII, HCGIV, HCGVIII and HCGIX containing a number of sequences displayed throughout the HLA Class I region. The presence of all these coding sequences and multigene families suggests that the gene density of the HLA Class I region is comparable to that of the class II and class III regions, i.e. one gene per 20 or 30 kb. We present here a new map compiling the update knowledge of the structure of this Class I region.