Genetic Control of Human

The serological analysis of h u m a n B cell a l loant igens has led to the def ini t ion of a HLAl i nked locus, des ignated H L A D R (1, 2), which codes for h u m a n Ia ant igens, i.e., h u m a n homologues o f m u r i n e Ia antigens. Thus far, 10 allospecificit ies have been assigned to this locus. Evidence has been accumula t ing over the past few years tha t h u m a n Ia ant igens are control led by at least two H L A l i n k e d loci. T h e first ind ica t ion was the discovery of a subset of Ia molecules car ry ing a n o n D R specificity DC1 by i m m u n o c h e m i c a l analysis at the molecular level (3). This d e t e r m i n a n t is cont ro l led by an allele at a separa te locus in s t rong l inkage d i sequ i l ib r ium wi th three alleles of the D R locus, DR1, DR2, and DRw6 (4, 5). S t ruc tu ra l charac te r iza t ion by microf ingerpr in t ing (6) and by two-dimensional electrophoresis (7) has shown tha t DC 1 molecules differ from D R molecules. This ident i f ica t ion of a second Ia locus has unvei led a basic homology of the h u m a n Ia system with the mur ine system in which two subsets of Ia molecules, I -A and I-E, exist (8). T h e e luc ida t ion of ano ther Ia specificity, BR4X7 (9) or H O N 7 (10), has revealed an add i t iona l complex i ty of the h u m a n Ia system. This specificity is cont ro l led also by an HLAl inked locus different from the D R locus and is t r ansmi t t ed in s t rong l inkage d isequi l ib r ium with the DR4, DR7, and D R w 9 alleles (5). BR4X7 could conceivably be allelic to DC 1 and thus be incorpora ted in a two-loci model . However , pep t ide m a p p i n g analysis showed that the molecules ca r ry ing B R 4 X 7 specificity are far more s imilar to D R molecules than to DC1 molecules, 1 lead ing to the assumpt ion tha t DC1 and BR4X7 m a y not be allelic. Consequent ly , a th i rd H L A l i n k e d Ia locus would be requi red to a c c o m m o d a t e BR4X7. Direct evidence for or against a three-loci hypothesis cannot be ob ta ined using the specificities DC1 and BR4X7 because they are always t r ansmi t t ed in repuls ion as a result of their associat ion with nonover l app ing sets of D R alleles. More comple te immunochemica l test ing of the three-loci concept requires the cons idera t ion of