The early expression of some human autoantibody-associated heavy chain variable region genes is controlled by specific regulatory elements

Abstract

Recent molecular cloning studies have revealed that some autoantibodies may be encoded directly by germline Ig variable (V) genes without any somatic mutation, suggesting strongly that such autoantibodies are physiologically important. Independent analyses of Ig gene expression in a human fetal liver showed that only nine heavy chain V (Vh) genes were used, out of a potential germline Vh gene repertoire of 100-200. We have observed that four of these nine Vh genes encode sequences identical or almost identical to human autoantibody heavy chains. This unexpected overlap implies that some autoantibodies are expressed preferentially during early development. Recent structural analyses of two Vh3 genes expressed in fetal liver revealed many more enhancer-like sequences in the flanking regions than expected for a typical Vh gene. It is hypothesized that these autoantibody-related Vh genes may contain various combinations of cis regulatory elements which influence their specific expression during early ontogenic development. Furthermore, these observations are consistent with network hypotheses, which suggest that early B-cell development is driven by reactivity with self. The cis regulatory elements in the autoantibody genes may act in concert with the positional effects that have been shown to facilitate Vh gene engagement.