Receptor editing in a mature, autoreactive B cell population

Abstract

Anergy, clonal deletion, and receptor editing are important mechanisms in maintaining tolerance in the immature B cell repertoire. While the role of receptor editing is an accepted mechanism in the immature population, secondary immunoglobulin rearrangements in mature B cells have been controversial. Although some data supporting receptor editing has been found in secondary lymphoid organs, the contribution of immature B cells in this observation has not been excluded. Moreover, many studies relied on the use of immunoglobulin transgenic models, in which the selection and migration of autoreactive lymphocytes may be altered.;We immunized non-autoimmune mice with a peptide mimetope of DNA. Previous work has shown that this treatment results in the production of anti-DNA antibodies and glomerular deposition of immunoglobulin in a lupus-like phenotype. Antigen-specific B cells from these mice were studied using avidity-enhanced fluorescent antigen tetramers. These cells have the phenotype of follicular B cells and express levels of costimulatory molecules and chemokine receptors consistent with B cells activated in a T dependent response. Many of these cells later acquire a memory cell phenotype. Analysis of the antigen-specific population revealed the expression of RAG mRNA and proteins, and the expression of both kappa and lambda light chains by many of the responding B cells. Immunization with a peptide that does not induce an autoreactive response did not induce RAG expression, and the responding cells remained allelically excluded.;Reports have indicated that mice with defects in apoptosis or with lymphoproliferative disorders can develop lupus-like diseases. Constitutive over-expression of Bcl-2 by B cells blocks clonal deletion in both the mature and immature populations. In the immature population, this results in enhanced receptor editing. In contrast, editing was not observed in mature B cells. We show here that the immunization of Bcl-2 transgenic mice with the DNA mimetope does not induce RAG expression in mature B cells. This provides additional evidence that mature and immature B cells differ in their response to autoreactivity, and suggests that apoptotic stimuli may play a role in the induction of secondary immunoglobulin rearrangement.