Jacob Chaim O, Yu Ning, Guo Shunhua, Jacob Noam, Quinn William J, Sindhava Vishal, Cancro Michael P, Goilav Beatrice, Putterman Chaim, Migone Thi-Sau, Stohl William
University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Arthritis Rheum. 2013 Apr;65(4):1043-54. doi: 10.1002/art.37846.
To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE).
Bcma-, Taci-, and Br3-null mutations were introgressed into NZM 2328 mice. NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry; for B cell responsiveness to BAFF by in vitro culture; for serum levels of BAFF and total IgG and IgG anti-double-stranded DNA (anti-dsDNA) by enzyme-linked immunosorbent assay; for renal immunopathology by immunofluorescence and histopathology; and for clinical disease.
BCMA, TACI, and B lymphocyte stimulator receptor 3 (BR3) were not surface-expressed in NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice, respectively. Transitional and follicular B cells from NZM.Br3-/- mice were much less responsive to BAFF than were the corresponding cells from wild-type, NZM.Bcma-/-, or NZM.Taci-/- mice. In comparison with wild-type mice, NZM.Bcma-/- and NZM.Taci-/- mice harbored an increased number of spleen B cells, T cells, and plasma cells, whereas serum levels of total IgG and IgG anti-dsDNA were similar to those in wild-type mice. Despite their paucity of B cells, NZM.Br3-/- mice had an increased number of T cells, and the numbers of plasma cells and levels of IgG anti-dsDNA were similar to those in wild-type mice. Serum levels of BAFF were increased in NZM.Taci-/- and NZM.Br3-/- mice but were decreased in NZM.Bcma-/- mice. Despite their phenotypic differences, NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice had renal immunopathology and clinical disease that were at least as severe as that in wild-type mice.
Any single BAFF receptor, including BR3, is dispensable for the development of SLE in NZM mice. Development of disease in NZM.Br3-/- mice demonstrates that BAFF-BCMA and/or BAFF-TACI interactions contribute to SLE, and that a profound, life-long reduction in the numbers of B cells does not guarantee protection against SLE.
确定任何一种个体BAFF受体在系统性红斑狼疮（SLE）发病中的必要性。
将Bcma、Taci和Br3基因敲除突变导入NZM 2328小鼠。通过流式细胞术评估NZM.Bcma-/-、NZM.Taci-/-和NZM.Br3-/-小鼠的淋巴细胞表型和BAFF受体表达；通过体外培养评估B细胞对BAFF的反应性；通过酶联免疫吸附测定评估血清中BAFF、总IgG和IgG抗双链DNA（抗dsDNA）水平；通过免疫荧光和组织病理学评估肾脏免疫病理学；以及评估临床疾病。
BCMA、TACI和B淋巴细胞刺激因子受体3（BR3）分别在NZM.Bcma-/-、NZM.Taci-/-和NZM.Br3-/-小鼠中未表面表达。与野生型、NZM.Bcma-/-或NZM.Taci-/-小鼠的相应细胞相比，NZM.Br3-/-小鼠的过渡性和滤泡性B细胞对BAFF的反应性要低得多。与野生型小鼠相比，NZM.Bcma-/-和NZM.Taci-/-小鼠的脾脏B细胞、T细胞和浆细胞数量增加，而总IgG和IgG抗dsDNA的血清水平与野生型小鼠相似。尽管NZM.Br3-/-小鼠的B细胞数量较少，但其T细胞数量增加，浆细胞数量和IgG抗dsDNA水平与野生型小鼠相似。NZM.Taci-/-和NZM.Br3-/-小鼠的血清BAFF水平升高，而NZM.Bcma-/-小鼠的血清BAFF水平降低。尽管它们的表型存在差异，但NZM.Bcma-/-、NZM.Taci-/-和NZM.Br3-/-小鼠的肾脏免疫病理学和临床疾病至少与野生型小鼠一样严重。
任何单一的BAFF受体，包括BR3，对于NZM小鼠SLE的发病都是可有可无的。NZM.Br3-/-小鼠疾病的发生表明BAFF-BCMA和/或BAFF-TACI相互作用促成了SLE，并且B细胞数量的显著、终生减少并不能保证预防SLE。
