Organisation génétique et polymorphismes de la région HLA-D

Abstract

Summary The HLA-D region contains several genes encoding proteins which, after glycosylation, constitute at least two class II molecules (human Ia: Iah), each composed of two chains (α and β). The region comprises at least 4 closely linked genes: DRα, DRβ, DCα and DCβ, the order of which is unknown. The first molecule described is DR, which carries the DR1 to DRw10 allelic series. It is composed of an α chain—which is not (or is only slightly) polymorphic (MW⋍34,000) — and a highly polymorphic β chain (MW⋍29,000) carrying the allospecificity. The DR molecule is the human homologue of the mouse IaE molecule. The DC molecule carries the DC1, 3 and 4 specificities (also called MB1, 2 and 3). It is made up of an α chain (MW⋍32,000) and a β chain (MW⋍28,000). Both chains are biochemically polymorphic, β more so than α. It is not known which chain carries the allotypic specificities. The DC (MB) molecule is homologous to the IaA murine molecule. A third allelic series with 3 specificities MT1, 2 and 3 (MT2 and MT3 are also called BR3 and BR4) could be carried by a third Iah molecule not yet formally demonstrated. Another possibility is that the 3 allelic series (DR, DC and MT) could be carried by two Iah molecules. The SB locus is centromeric to HLA-DR, from which it is separated by recombination. Its product is an Iah molecule made up of an SBβ chain (demonstrated) associated with an SBα chain (postulated). Five SB allelic forms initially recognized by secondary MLR have been described. Some of these were also serologically detected. SB is similar in structure and function to DR and DC and thus has to be included in an enlarged HLA-D region. The HLA-D region initially defined by a cellular technique (primary MLR), was then analysed by biochemical and serological methods. The relationship between a postulated HLA-Dw product defined by cellular techniques and DR and DC products serologically detected, remains controversal. One interpretation would be that there is no HLA-Dw product per se, and that the HLA-Dw phenotype defined by primary MLR is the result of the allotypic make-up of the DR, DC and perhaps SB molecules carried by the cells present in the MLR. According to this hypothesis, HLA-Dw would be composed of multiple determinants, one of which (DR) could be immunodominant. The biochemical and allotypic analysis of the products of the HLA-D region are important in the understanding of their biological role: presentation of the exogenous antigen to the T cells, and thus regulation of the immune response. A more detailed analysis of the allogeneic response can now be made and applied to the definition of a better histocompatibility for kidney or bone marrow transplantation.