title: The Effect of BAFF Inhibition on Autoreactive B-Cell Selection in Murine Systemic Lupus Erythematosus.
abstract: The goal of this study was to determine how B-cell-activating factor of the TNF family (BAFF) availability influences selection of the autoreactive B-cell repertoire in NZB/W and NZW/BXSB lupus-prone mice bearing the site-directed heavy-chain transgene 3H9 that encodes for anti-dsDNA and anti-cardiolipin (CL) autoantibodies. We used a bone marrow chimera system in which autoreactive 3H9 transgenic B cells were allowed to mature in competition with wild-type cells and could be identified by green fluorescent protein. The light-chain repertoire associated with the 3H9 heavy chain in naive and antigen-activated B-cell subsets was assessed using single-cell polymerase chain reaction. We found that deletion of autoreactive transgenic B cells occurred in the bone marrow of both strains regardless of BAFF availability, and there were only modest and physiologically non-relevant effects on the naive B-cell repertoire. BAFF inhibition had different effects on selection of the germinal center repertoire in the two strains. In the NZW/BXSB strain, BAFF inhibition phenocopied the loss of one TLR7 allele in that it influenced the selection of 3H9-encoded autoreactive B cells in the germinal center but did not prevent somatic mutation. In the NZB/W strain, BAFF inhibition did not alter the selection of 3H9-encoded B cells in the germinal center, but it influenced selection of a subset of germinal center cells into the plasma cell compartment. Our data underscore the complexity of regulation of the autoreactive B-cell repertoire by BAFF and may help to explain the heterogeneity of responses observed after BAFF inhibition in humans.
authors.affiliation: Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Alexis
authors.initials: A
authors.lastname: Boneparth
authors.affiliation: Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Woods
authors.affiliation: Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Huang
authors.affiliation: Musculoskeletal Diseases and Biostatistics Unit, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Meredith
authors.initials: M
authors.lastname: Akerman
authors.affiliation: Musculoskeletal Diseases and Biostatistics Unit, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Lesser
authors.affiliation: Center for Autoimmunity, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Davidson