There is evidence that certain alleles at the HLA-DQ locus are correlated with susceptibility to insulin-dependent diabetes mellitus (IDDM) and in particular that DQ beta-chain alleles containing aspartic acid at position 57 are protective. The availability of a large group of patients with IDDM enabled us to assess the role of HLA-DQ alleles in susceptibility to the disease in order to confirm and extend recent observations derived from studies of smaller numbers of patients. Using allele-specific oligonucleotide probes and the polymerase chain reaction, we studied 266 unrelated patients with IDDM and 203 unrelated normal subjects for eight HLA-DQ beta-chain alleles. Two major findings emerged from these studies. First, the presence of an HLA-DQw1.2 allele was protective. Only 6 of the 266 patients with IDDM (2.3 percent) were positive for HLA-DQw1.2, as compared with 74 of the 203 normal subjects (36.4 percent; P less than 0.001). Thus, persons with the HLA-DQw1.2 allele, which is one of the polymorphic forms of the beta chain of the HLA-DQ molecule, rarely had IDDM, no matter which other HLA-DQ beta-chain allele they inherited ("dominant protection"). Second, the presence of the HLA-DQw8 allele increased the risk of IDDM. The relative risk of IDDM was 5.6 in persons homozygous for HLA-DQw8, and it was similar in persons with the HLA-DQw1.1/DQw8 or HLA-DQw2/DQw8 haplotype ("dominant susceptibility"). However, the relative risk of IDDM in persons who had the HLA-DQw1.2/DQw8 haplotype was 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. We conclude that the presence of the HLA Class II antigen DQw1.2 is strongly protective against the development of IDDM, and that complete HLA-DQ typing is necessary for accurate assessment of susceptibility to IDDM.

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Monoclonal antibody IVD12 was used to isolate and characterize a human Ia molecule present on B cells that generally display DR4 or DR5 phenotypes. The specificity of binding of IVD12 to human peripheral blood B cells from 75 normal individuals and 19 homozygous human lymphoblastoid B cell lines was identical to the supertypic specificity MB3 previously defined. Furthermore, IVD12-reactivity was shown to segregate with HLA in three informative families. In each family, individuals positive for IVD12 binding were also positive for DR4 or DR5. Using IVD12, a molecule has been isolated from the homozygous cell line PRIESS (DR4/4) and has been shown by amino acid sequence analysis to be homologous to the murine I-A and human HLA-DS molecules. These findings suggest that the MB3 specificity is found on a molecule encoded by loci distinct from those loci which encode HLA-DR molecules. This molecule represents the third family of HLA-D region molecules isolated from the cell line PRIESS. Both HLA-DR and HLA-SB molecules from this cell line were previously shown by amino acid sequence analysis to be I-E-like but distinct from one another. Collectively, these data provide evidence that the HLA-D region contains at least six loci encoding distinct alpha and beta chains for the HLA-SB, HLA-DR, and HLA-DS molecules.

The antigens encoded in the HLA-D region of the human major histocompatibility complex (MHC) 1 were originally defined with homozygous typing cells by mixed leukocyte culture and, subsequently, by use of human alloantisera reacting with antigens selectively expressed on B cells (1, 2). These antigens were later shown to be the human equivalents of the murine Ia molecules. The major serologically defined specificities, called DR, were found to be closely associated with the specificities defined by HTCs. Later, the development of ailoantisera permitted identification of additional serologic specificities such as DC, MB, MT, and Te (3-8) which are not associated with a single DR specificity but, instead, are found associated with two or more DR alleles and are, therefore, called supertypic. For example, MT2 is usually found on DR3-, DR5-, DRw6-, or DRw8-bearing cells while MT3 is usually found on cells from DR4-, DR7-, or DRwg-positive donors. The apparent equivalence of terms used by different investigators is shown in Table I (see also reference 3).Studies of the structural bases for these serological specificities have focused on three types of molecules that have been described biochemically. In a total Ia isolate, DR molecules are the predominant set of HLA-D region antigens and are homologues of the murine I-E molecules (9). These molecules bear the DR serologic specificities, which have been shown to be associated with their polymorphic beta chains (9). A DR homozygous cell line expresses DR molecules that are a set of closely related proteins which appear to share a single alpha chain and possess several structurally distinct beta chains (10, 1 1). It is not clear if all of these 1-E-like species carry the DR serologic determinants that are defined with alloantisera. The DS (DC) antigens are homologues of the murine I-A antigens (12) and bear the MB serologic determinants (13,14).