Biochemical aspects of human Ia molecules

Abstract

In the past few years considerable attention has been addressed to the biochemical analysis of the human Ia molecules in order to set the necessary background for the correct understanding of the biological function of such a highly complex system. The purpose of this section is to discuss the available informations on the biosynthesis, expression, and structural heterogeneity of the class II molecules. Human Ia antigens are cell surface glycoproteins composed of two subunits and/3, of apparent molecular weight of 34-36 Kd and 26-29 Kd, respectively. In reviewing the current knowledge of the steps leading to their expression on the cell surface, Michael Owen from ICRF in London presented evidence that c~ and /3 chains are synthesized as precursors with signal sequences. Five minutes after their synthesis the two subunits are already assembled and partially glycosylated in the Rough Endoplasmic Reticulum. At this period the Invariant (In) chain, a third glycoprotein of apparent molecular weight of 31-33 Kd, is associated to the ~-3 heterodimer. In the following 25-30 min the ~-In-/3 complex is processed to mature forms (two N-linked oligosaccarides for the ~ and In chain and one for the/3 chain) and transported to the cell surface where the In chain is no longer detectable. The biological role of such glycoprotein synthesized in a fivefold excess with respect to the a and 13 subunits remains unclear. Dominique Charron from Paris presented evidence of nonpolimorphism of the In chain both in mouse and in man. Two-dimensional electrophoresis showed that the murine species is slightly more basic than the human counterpart. Moreover, peptide map analysis revealed strong similarities between In chains of the two species. The attention was then focused on the biochemical evidence of polymorphism and heterogeneity of the human Ia antigens. Historically, in addition to the classical polymorphic DR system, serological and cellular typing have suggested the existance of a considerable number of antigenic systems namely: BR,DC,LB,MB,MT,SB. As far as the DR molecules were concerned, there is now a general consensus in assigning to the 13 subunit the characteristics of polimorphic entity. Do the other specificities correspond to distinct molecular structures and, if so, which subunit carry polymorphic characteristics? By using an exclusively biochemical approach, Kratzin and colleagues (see this volume) have presented evidence of the existence of at least seven 13 chains and 2 ~ chains all different from one another as judged by aminoacid analysis. It is important to note that the Ia pool analyzed by Kratzin derived from a DR 2 homozygous cell line. Therefore this finding demonstrates a multiplicity o f /3 chain genes not due to allelic forms of a single locus. The results obtained by other groups also pointed to the existence of distinct subsets. The results made use of biochemical and immunochemical combined