SB: a new HLA-linked human histocompatibility gene defined using HLA-mutant cell lines

Abstract

Although the genes of the major histocompatibility complex (MHC) are tightly linked, four loci (HLA-A, B, C and DR) have been defined using rare families in which antigenic specificities segregated from each other. As an alternative approach for defining loci, Kavathas et al.¹ selected HLA-mutant lymphoblastoid cell lines (LCLs) that had lost expression of specific genetic markers. An HLA-GLO heterozygous LCL, LCL-721, was mutagenized with ionizing radiation which is known to induce multigenic deletions²; variants no longer expressing a specific HLA antigen were selected. While some mutants lost expression of only the antigen selected against, most simultaneously lost expression of several identifiable cis-linked gene products. Many of the multiple-loss mutants resulted from chromosome rearrangements, especially deletions¹. Five new secondary B-cell (SB) antigens have recently been defined^3,4, which evoke strong secondary allogeneic proliferative and cytotoxic responses. Because they resemble the HLA-DR antigens both functionally and genetically, it was not known whether they were coded for by a gene distinct from the gene(s) encoding HLA-DR. We have now characterized LCL-721 mutants for expression of both HLA-DR and SB. Of 20 lines which had lost expression of the HLA-A, -B and -DR antigens from one haplotype, four retained expression of the cis-linked SB antigen. One of these mutants had a visible deletion that included the region coding for HLA on the short arm of one chromosome 6. Because the cis-linked SB antigen continued to be expressed, the gene coding lor SB antigens must be different from that coding for HLA-DR antigens.