BeO-exposure induces B cell-mediated Noninfectious Granuloma Formation in the Lung

Abstract

Abstract Susceptibility to chronic beryllium disease (CBD)is linked to HLA-DP molecules possessing a glutamic acid at the 69thposition of the β-chain (βGlu69), with the most prevalent βGlu69-containing molecule being HLA-DP2. We have previously shown that exposure of HLA-DP2 transgenic mice to beryllium oxide (BeO) results in the development of mononuclear infiltrates in a peribronchovascular distribution and a beryllium-specific, HLA-DP2-restricted CD4+T cell response. In addition to T cells, B cells constituted a major portion of infiltrated leukocytes in the lung of BeO-exposed HLA-DP2 Tg mice and were localized within ectopic lymphoid aggregates and granulomas. B cell depletion had no effect on the development of Be-specific CD4+T cells. However, B cell depletion was associated with a loss of lymphoid aggregates and granulomas as well as a significant increase in lung injury in BeO-exposed mice compared to the isotype-treated group. Furthermore, B cell recruitment to the lung was independent of antigen and dependent on MyD88 signaling through the secretion of CXCL13. Adoptively-transferred WT B cells into BeO-exposed μMT mice significantly reduced lung injury. B cells also surrounded granulomas in transbronchial biopsies from CBD patients, confirming a role for B cells in CBD. Overall, our data suggest a novel modulatory role for B cells in the formation of granulomas and lymphoid aggregates, resulting in the protection of the lung against sterile particulate exposure.