Neutrophils Contribute to Excess Serum BAFF Levels and Promote CD4+ T Cell and B Cell Responses in Lupus-Prone Mice

Abstract

Despite increased frequencies of neutrophils found in autoimmune diseases such as systemic lupus erythematosus (SLE), how they contribute to disease pathogenesis and the mechanisms that affect the accumulation of neutrophils are poorly understood. The aim of this study was to identify factors in autoantibody-mediated autoimmunity that controls the accumulation of spleen resident neutrophils and to determine whether neutrophils contribute to abnormal B cell responses. Increased levels of the cytokine BAFF have been linked to loss of B cell tolerance in autoimmunity, but the cellular source responsible for excess BAFF is unknown. B cell maturation antigen (BCMA) is a receptor for BAFF and is critical for the survival of bone marrow plasma cells. Paradoxically, BCMA deficiency exacerbates the formation of autoantibody-secreting plasma cells in spleens of lupus-prone mice and the reasons for this effect are not understood. Here we analyzed the phenotype, localization and function of neutrophils in spleens of healthy mice and congenic lupus-prone mice, and compared mice sufficient or deficient in BCMA expression. Neutrophils were found to be significantly increased in frequency and activation status in spleens of lupus-prone mice when BCMA was absent. Furthermore, neutrophils localized within T cell zones and enhanced CD4+ T cell proliferation and IFNγ production through the production of BAFF. Reduced BAFF and IFNγ serum levels, decreased frequencies of IFNγ-producing T cells, germinal center B cells, and autoantibody production after neutrophil depletion indicated the involvement of neutrophils in these autoimmune traits. Thus, we have identified a novel role for BCMA to control excess BAFF production in murine lupus through restraining the accumulation of BAFF-producing neutrophils. Our data suggests that devising therapeutic strategies to reduce neutrophils in autoimmunity may decrease BAFF levels and ameliorate disease.

Splenic Marginal Zone Granulocytes Acquire an Accentuated Neutrophil B-Cell Helper Phenotype in Chronic Lymphocytic Leukemia

“…Neutrophils localized to the RP and MZ, a distribution that was clearly distinguishable from autoinflammatory processes where neutrophils can be located in the T-cell zone (53). Depletion of neutrophils in Em-Tcl1 mice delayed leukemia proliferation associated with the upregulation of the cell-cycle inhibitor Egr1 and the differentiation factor Egr2 (25,26).…”

Alterations in DNA methylation corresponding with lung inflammation and as a biomarker for disease development after MWCNT exposure

“…Increases in neutrophil infiltration have been shown to enhance IFN-γ production through the production of B-cell activating factor (Coquery et al, 2014). While changes in IFN-γ production were not observed at 24 h in this study, it is possible that this cytokine is latently activated after neutrophil recruitment.…”

The role of BAFF in the progression of rheumatoid arthritis

“…Tnfrsf17À/À mice treated with the inflammatory agent pristine showed TFH cell accumulation, indicating that BCMA reduces the expansion of TFH cells and the development of autoimmunity. Coquery and his team reported that in lupus-prone mice with BCMA deficiency, the activation status and neutrophil accumulation were found to be increased significantly in the spleen tissues [46].…”