The IgVκ gene encoding anti-DNA autoantibody and its receptor editing in patients with SLE

Abstract

A germline IgVκ gene, A 30 is preferentially used for antibodies against selfantigens including DNA. A 30 may thus be autoantibody associated IgVκ gene. The A 30 gene is receptor edited in circulating B lymphocytes from normal individuals. SLE B lymphocytes failed to edit the A 30 gene, leading to the production of anti DNA autoantibody. Recombination activating gene (RAG) expression is essential for the receptor editing. Thus, expression of RAG proteins by peripheral blood mature B lymphocytes of normal subjects and patients with SLE has been analyzed. Normal B cells did not express RAG proteins spontaneously, and after activation withStaphylococcus aureusand IL-2, the B cells expressed RAGs. Recombination signal sequence (RSS) binding activity was verified by a gel shift assay in the nuclear proteins of activated B cells. Usage of a most downstream Jκ, Jκ 5, was evident in activated B cells expressing RAGs. λ chain and intracellular RAGs were simultaneously expressed on the purified κ + B cells after activation. Both findings suggest secondary light chain rearrangement in mature B cells. Some of RAG-expressing B cells could have failed in productive secondary rearrangement and they died via apoptosis. Thus, RAG expressing B cells would revise their surface Ig or would die, leading to elimination of the autoreactive B cells.We found that anti-DNA autoantibody secreting B cells in patients with SLE did not express RAG spontaneously nor even after activation. Thus anti-DNA secreting B cells did not revise their Ig gene nor die via apoptosis, causing them to develop and persist autoantibody secretion by SLE B cells. These results suggest that failure of RAG reexpression in anti-DNA secreting B cells may be important for autoantibody production of SLE patients.