Coquery Christine M, Wade Nekeithia S, Loo William M, Kinchen Jason M, Cox Kelly M, Jiang Chao, Tung Kenneth S, Erickson Loren D
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America.
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America.
PLoS One. 2014 Jul 10;9(7):e102284. doi: 10.1371/journal.pone.0102284. eCollection 2014.
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.
尽管在系统性红斑狼疮（SLE）等自身免疫性疾病中发现中性粒细胞的频率增加，但它们如何促进疾病发病机制以及影响中性粒细胞积累的机制仍知之甚少。本研究的目的是确定自身抗体介导的自身免疫中控制脾脏驻留中性粒细胞积累的因素，并确定中性粒细胞是否促成异常的B细胞反应。细胞因子BAFF水平升高与自身免疫中B细胞耐受性丧失有关，但负责过量BAFF的细胞来源尚不清楚。B细胞成熟抗原（BCMA）是BAFF的受体，对骨髓浆细胞的存活至关重要。矛盾的是，BCMA缺陷会加剧易患狼疮小鼠脾脏中分泌自身抗体的浆细胞的形成，而这种效应的原因尚不清楚。在这里，我们分析了健康小鼠和同基因易患狼疮小鼠脾脏中中性粒细胞的表型、定位和功能，并比较了BCMA表达充足或缺陷的小鼠。当不存在BCMA时，发现易患狼疮小鼠脾脏中的中性粒细胞频率和激活状态显著增加。此外，中性粒细胞定位于T细胞区，并通过产生BAFF增强CD4(+) T细胞增殖和IFNγ产生。中性粒细胞清除后，BAFF和IFNγ血清水平降低，产生IFNγ的T细胞、生发中心B细胞频率降低，自身抗体产生减少，表明中性粒细胞参与了这些自身免疫特征。因此，我们确定了BCMA在小鼠狼疮中通过抑制产生BAFF的中性粒细胞的积累来控制过量BAFF产生的新作用。我们的数据表明，设计减少自身免疫中中性粒细胞的治疗策略可能会降低BAFF水平并改善疾病。
