Chronic graft-versus-host reaction is associated with a decrease in Ig light chain receptor editing in bone marrow...

The encounter of developing B cells in the bone marrow with soluble hen egg lysozyme (sHEL) self antigen induces anergy and endogenous kappa light chain rearrangements ('receptor editing'). We have previously shown that induction of chronic graft-versus-host reaction (GVH) in tolerant Ig/sHEL mice results in prevention of B cell anergy in the bone marrow and the spleen. We now report that in chronic GVH, immature self-reactive B cells also show reduced levels of receptor editing in the bone marrow. This is evidenced by the following observations: (a) a small population of'receptor-edited' B cells, which is found in tolerant mice, is markedly reduced in mice that have lost tolerance in chronic GVH; (b) self-reactive B cells in GVH mice have reduced levels of endogenous kappa chain rearrangements; and (c) recombinase-activating gene (RAG)-2 expression is markedly decreased in immature self-reactive B cells in the bone marrow of chronic GVH mice. These results suggest that in chronic GVH newly emerging B cells escape tolerance, in part because of decreased receptor editing in the bone marrow. Thus, the autoimmunity induced by chronic GVH may ultimately result from the failure of B cell tolerance at multiple checkpoints.