Induction of Regulatory B Cells by Bacterial DNA in the Gut Microbiota at Early Age is Beneficial in Lupus-prone Mice

Abstract

Abstract SLE is a complex autoimmune disorder with no known cure. We previously reported that oral vancomycin treatment of female MRL/lpr mice during active disease (9 to 15 weeks of age) could significantly ameliorate disease symptoms. However, when vancomycin treatment was initiated from an earlier age (from 3 to 15 weeks), the beneficial effect was not observed. Strikingly, mice given vancomycin during the pre-disease stage (from 3 to 8 weeks) exhibited exacerbated lupus disease. As vancomycin works by removing parts of the gut microbiota, we hypothesized that the regulatory immunity induced by gut microbiota at early age is essential in hammering lupus disease development in MRL/lpr mice. To test the hypothesis, we analyzed diverse regulatory cell types from the mice receiving vancomycin from 3 to 8 weeks of age. Regulatory B (Breg) cells, in particular, were found to be reduced in both the percentage and absolute number in multiple lymphoid organs. Importantly, adoptive transfer of Breg cells at 6–7 weeks of age to long-term vancomycin-treated mice improved lupus-like symptoms. This clearly indicates that Breg cells, inducible by vancomycin-sensitive gut microbiota, plays an important role in suppressing lupus disease initiation and progression. We next sought to determine Breg inducers in the gut microbiota. The serum level of bacterial DNA was found to be significantly lower in mice treated with vancomycin. More importantly, early administration of bacterial DNA reproduced the beneficial effect seen in the Breg adoptive transfer experiment. Together, these results suggest an important protective mechanism against lupus initiation that involves bacterial DNA in the gut microbiota and the induction of Breg cells.