Helminth-induced B lymphocytes mediate control of IL-17 and emphysema through their production of RELMα

Abstract The intestinal nematode parasite, Nippostrongylus brasiliensis (Nb), can cause emphysema and the mechanisms remain poorly defined. Here we show that emphysema develops as early as 7 days after Nb inoculation and is associated with increased gene expression of Il17a, as well as increases in type 2 cytokines Nb infection of Il17a−/− mice results in a less severe emphysematous pathology, and decreased neutrophil influx to the lung, with little effect on the development of the type 2 immune response. Surprisingly, Nb infection of B cell deficient Jh−/− mice results in a more severe emphysema at day 7, and as late as day 30, and is associated with higher numbers of neutrophils and increased expression of Il17a in the lung. Most of the B cells in the lung are B2 regulatory cells and are activated through IL-4R signaling. However, IL-10 and other regulatory cytokines typically associated with B regulatory cell function did not play a major role in this response. Instead, at early stages of the response B cells produced high levels of RELMa. Transfer of B lymphocytes from WT mice or Il10−/− mice, but not from Il4Rα−/− mice, or Relmα−/− mice to recipient Jh−/−mice restored the control of emphysema, decreased the influx of neutrophils, and downregulated IL-17A. Although macrophages also expressed RELMa, it was not upregulated until 4 days after inoculation, whereas B cells upregulated RELMa as early as day 3. These studies show that elevations in IL-17 trigger emphysematous pathology and reveal a novel role for helminth-induced B cells in controlling IL-17A and the severity of emphysema through their production of RELMa.