Abstract
OBJECTIVE: We assessed the contributions of B cell and T cell subsets to the disparate clinical outcomes in NZM.Baff(-/-) and NZM.Br3(-/-) mice. METHODS: We assessed in NZM wild-type, NZM.Baff(-/-), and NZM.Br3(-/-) mice numbers and percentages of B cells and subsets, T cells and subsets, and in vivo proliferation and survival of forkhead box P3 (Foxp3)(+) cells by fluorescence-activated cell sorting. Relationships between percentages of Foxp3(+) cells and numbers of CD19(+) and CD4(+) cells were assessed by linear regressions. RESULTS: In each age and sex cohort, percentages and numbers of CD19(+) cells were similar in NZM.Baff(-/-) and NZM.Br3(-/-) mice. Percentages of CD3(+) and CD4(+) cells were greater in NZM.Br3(-/-) than in NZM.Baff(-/-) mice, with the CD4 to CD3 cell ratios being greater in NZM.Br3(-/-) than in NZM.Baff(-/-) mice and percentages of Foxp3(+) cells in NZM.Br3(-/-) mice being lower than in NZM.Baff(-/-) mice. Percentages of Foxp3(+) cells correlated positively with CD19(+) cells in NZM.Baff(-/-) mice but negatively in NZM.Br3(-/-) mice. In vivo proliferation and survival of Foxp3(+) cells were lower in NZM.Baff(-/-) mice than in NZM.Br3(-/-) mice. CONCLUSION: Differences between NZM.Baff(-/-) and NZM.Br3(-/-) mice in Foxp3(+) cells and their relationships with CD19(+) cells may have more to do with their divergent clinical outcomes than do differences in numbers of B cells. These unexpected findings suggest that B cell activating factor (BAFF)-B cell maturation antigen (BCMA) or BAFF-Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) interactions may help drive development of clinical systemic lupus erythematosus (SLE) even under conditions of considerable B cell depletion. Insufficient blocking of BAFF-BCMA and BAFF-TACI interactions may lie at the heart of incomplete clinical response to BAFF-targeting agents in human SLE.