SKEWED V-H AND V-KAPPA GENE FAMILY EXPRESSION AND PAIRING OCCURS AMONG B-LYMPHOCYTES IN AUTOIMMUNE MOTH-EATEN MICE

Motheaten mice homozygous for the recessive me(v) mutation develop a f atal immunodeficiency syndrome associated with hypergammaglobulinemia, thymic aplasia, production of autoantibodies and development of a sev ere lupus like systemic autoimmune disease. Most B lymphocytes in this mutant strain belong to B-1 subset. We have addressed the question if differences existed in the V-gene repertoire of autoimmune me(v)/me(v ) mice as compared to phenotypically normal me(v) + and C57BL/6 backgr ound strain by examining the V-H and V-kappa gene family expression as well as the association of V-H and V-kappa gene families among B lymp hocyte clones. The data outlined here demonstrate that both the expres sion of V-H and V-kappa gene families and their association is skewed in me(v)/me(v) mice, suffering from systemic autoimmune disease, and d iffers significantly from phenotypically normal me(v)/+ litter mates a s well as the C57BL/6 background strain. In addition, V-H + V-kappa ge ne family pairs in phenotypically normal me(v)/+ differed from normal C57BL/6 mice suggesting that motheaten mutation, whether homozygous or heterozygous, alters the development of the B lymphocyte repertoire. These observations suggest positive selection of B-1 lymphocytes in au toimmune motheaten mice either as a result of selective processes, via receptor-ligand interactions, operating on the development of the pri mary antibody repertoire or defective B lymphocyte haematopoiesis due to the deficiency of haematopoietic cell phosphatase involved in deter mining the threshold by which B cells respond to self antigen(s).