B1-like B cells derived from the bone marrow and not fetal-derived B1 B cells are responsible for the protective IgE induced in helminth infection

Abstract

Abstract Nippostrongylus brasiliensis (Nb) is the strongest natural inducer of IgE. Despite this fact, asthma rates have an inverse correlation in countries endemic with parasitic infection, and multiple groups have shown that helminth infection has a protective phenotype in murine asthma. In a previous publication our lab showed that innate-like B1 B cells produced IgE in response to Nb infection and this IgE inhibits helminth clearance in a mast cell (MC) dependent manner. Therefore we hypothesized that the reduction in helminth clearance and the protective phenotype in asthma was driven by B1 B cell IgE preventing MC degranulation. To test this, we utilized a four week model of murine asthma and injected IgE anti-DNP as our “benign” IgE bi-weekly. Treatment significantly improved the outcomes associated with this model. Excited by these data we sought to further define the transcriptional differences between B1 and B2 B cells before and after Nb infection using RNAseq analysis. We found that gene expression in peritoneal (PL) B2 B cells were more similar to PL B1 B cells than to lymph node resident B2 B cells, both before and after Nb infection. Next, we sought a better way to separate B1 and B2 B cells than traditional cell surface markers. Utilizing a lineage specific reconstitution model where fetal derived B1 B cells made FLAG-tagged IgE and bone marrow (BM) derived B2 B cells made untagged IgE, we demonstrated that fetal derived B1 B cells were not responsible for Nb-induced IgE. Using the same reconstitution system, we showed that BM derived B cells that express B1 B cell surface markers were a significant source of Nb-induced IgE. Overall, we show that protective Nb-induced IgE is produced by B1-like B cells derived from the BM and not fetal-derived B1 B cells. Funding: This work was supported by funding from VCU’s CTSA (UL1TR002649 from the National Center for Advancing Translational Sciences) to R.K.M. and the CCTR Endowment Fund of VCU as well as funding from NIAID-NIH (R56AI139658) to RKM. Services used were supported, in part by the NIHNCI Cancer Cancer Support Grant P30 CA016059.