Genes responsible for quantitative regulation of antibody production

Evidence is first presented demonstrating that the individual capacity for antibody responsiveness has an inheritable component. The main evidence consists of spontaneous mutations causing either immunodeficiency or predisposition to autoimmunity in human and animals, and the involvement of some obvious candidate genes (in particular those belonging to the highly polymorphic histocompatibility and Igh loci), extensively analyzed in many mouse strain combinations. One finding constantly emerging from these studies is that single gene expression depends on environmental effects, lowering the genotype/phenotype correlation, but also on multigenic interactions appearing as background effects. The models available for the analysis of this multigenic regulation are discussed with special emphasis on the high and low antibody responder mice produced for this purpose by bidirectional selective breeding. The major advantage of this model is that the interline difference is huge and multispecifically expressed. The second part of the review presents the recent results on positional mapping of genes with immunomodulatory effects in this model and in one appropriate recombinant congenic strain series. This in vivo genetic dissection of antibody responsiveness discriminated the involvement of candidate genes and suggested that unsuspected genes might be identified by means of this wide open search.