HLA ‘help’ for human B2-microglobulin across species barriers

Abstract

HLA antigens comprise products of what is commonly considered to be one of the most polymorphic systems presently known, occurring on chromosome 6. The HLA epitope is present only once¹ on a glycoprotein of molecular weight 45,000. In its naturally occurring form it is tightly, and probably obligatorily, but non-covalently bound to B2-microglobulin, (B2M), a protein of molecular weight 11,600 (ref. 2), determined by chromosome 15. B2M has substantial sequence homology with the C_H3 domain of IgG (ref. 3), and seems to be non-polymorphic. Precisely analogous associations occur between several other MHC antigens in rodents and fowl, and the equivalents of B2M in those species. This leads to the question as to why products of probably the most polymorphic systems should be so strongly associated with a non-polymorphic protein. In this paper we confirm that human B2M is immunogenic in phylogenetically distant species when the molecule is presented alone. When the species barrier is close, immunogenicity declines drastically as, for example, between man and other primate. In contradistinction, however, when B2M is presented bound to the HLA alloantigen-bearing chain, as occurs naturally, the complex is exquisitely immunogenic with respect to both B2M and the alloantigenic determinant if the species are closely related, and may decline as the species barrier widens. This is interpreted in terms of a modified ‘intramolecular’ help effect across a phylogenetically closely related barrier.