Autoantibodies and the fetal antibody repertoire

Developing fetal B cells preferentially rearrange a restricted subset of the encoded antibody gene segments. There are striking structural similarities between elements expressed early in man and in mouse, most evident on comparison of murine VH elements from the VH7183 family to human VH elements of the VH3 family. The similarity is pronounced in two framework regions which together encode a possible binding site that is distinct from the classical antigen-combining site. By comparing all known human and murine VH gene sequences, we have demonstrated that these regions have been conserved in a family-specific manner throughout the mammalian radiation. The "non-conserved" spacer of the recombinase recognition signal is also highly conserved in a family-specific manner, suggesting a mechanism by which the expression of family-dependent features may be regulated. The evidence that such features contribute to the high incidence of self- and poly-specificity in the fetal antibody repertoire is reviewed.