Skewed V_H and V_K Gene Family Expression and Pairing Occurs Among B Lymphocytes in Autoimmune Motheaten Mice

Abstract

Motheaten mice homozygous for the recessive me^v mutation develop a fatal immunodeficiency syndrome associated with hypergammaglobulinemia, thymic aplasia, production of autoantibodies and development of a severe lupus like systemic autoimmune disease. Most B lymphocytes in this mutant strain belong to B-l 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 background strain by examining the V_H and V_K gene family expression as well as the association of V_H and V_K gene families among B lymphocyte clones. The data outlined here demonstrate that both the expression of V_H and V_k gene families and their association is skewed in me^v/me^v mice, suffering from systemic autoimmune disease, and differs significantly from phenotypically normal me^v/ + litter mates as well as the C57BL/6 background strain. In addition, V_H + V_K gene 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-l lymphocytes in autoimmune motheaten mice either as a result of selective processes, via receptor-ligand interactions, operating on the development of the primary antibody repertoire or defective B lymphocyte haematopoiesis due to the deficiency of haematopoietic cell phosphatase involved in determining the threshold by which B cells respond to self antigen(s).

Key Words:

• Au to supply