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本文引用的文献

1
Purification and immune phenotyping of B-1 cells from body cavities of mice.从小鼠体腔中纯化B-1细胞并进行免疫表型分析。
Methods Mol Biol. 2014;1190:17-34. doi: 10.1007/978-1-4939-1161-5_2.
2
Splenic B-1a Cells Expressing CD138 Spontaneously Secrete Large Amounts of Immunoglobulin in Naïve Mice.脾脏 B-1a 细胞在幼稚小鼠中自发表达 CD138 并大量分泌免疫球蛋白。
Front Immunol. 2014 Mar 28;5:129. doi: 10.3389/fimmu.2014.00129. eCollection 2014.
3
Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.两种功能性狼疮相关 BLK 启动子变异体控制细胞类型和发育阶段特异性转录。
Am J Hum Genet. 2014 Apr 3;94(4):586-98. doi: 10.1016/j.ajhg.2014.03.008.
4
Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice.B淋巴细胞激酶（Blk）表达降低会增强促炎细胞因子的产生，并在C57BL/6-lpr/lpr小鼠中诱发肾病。
PLoS One. 2014 Mar 17;9(3):e92054. doi: 10.1371/journal.pone.0092054. eCollection 2014.
5
Do follicular dendritic cells regulate lupus-specific B cells?滤泡树突状细胞是否调节狼疮特异性 B 细胞？
Mol Immunol. 2014 Dec;62(2):283-8. doi: 10.1016/j.molimm.2014.02.010. Epub 2014 Mar 14.
6
Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis.信号转导和转录激活因子4（STAT4）基因多态性与狼疮性肾炎严重肾功能不全的相关性
PLoS One. 2013 Dec 27;8(12):e84450. doi: 10.1371/journal.pone.0084450. eCollection 2013.
7
Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome.多个与先天和适应性免疫反应都有关的位点的变异与干燥综合征有关。
Nat Genet. 2013 Nov;45(11):1284-92. doi: 10.1038/ng.2792. Epub 2013 Oct 6.
8
Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders.皮肌炎的全基因组关联研究揭示了与其他自身免疫性疾病的遗传重叠。
Arthritis Rheum. 2013 Dec;65(12):3239-47. doi: 10.1002/art.38137.
9
Advances in lupus genetics.狼疮遗传学的进展。
Curr Opin Rheumatol. 2013 Sep;25(5):561-8. doi: 10.1097/BOR.0b013e328363eb4e.
10
Circulating phenotypic B-1 cells are decreased in common variable immunodeficiency and correlate with immunoglobulin M levels.循环表型 B-1 细胞在普通变异性免疫缺陷中减少，并与免疫球蛋白 M 水平相关。
Clin Exp Immunol. 2013 Mar;171(3):278-82. doi: 10.1111/cei.12008.

小鼠和人类中B1细胞亚群增加与狼疮表型的一致性取决于BLK表达水平。

Concordance of increased B1 cell subset and lupus phenotypes in mice and humans is dependent on BLK expression levels.

作者信息

Wu Ying-Yu, Georg Ina, Díaz-Barreiro Alejandro, Varela Nieves, Lauwerys Bernard, Kumar Ramesh, Bagavant Harini, Castillo-Martín Mireia, El Salem Fadi, Marañón Concepción, Alarcón-Riquelme Marta E

机构信息

Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;

Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada 18016, Spain;

出版信息

J Immunol. 2015 Jun 15;194(12):5692-702. doi: 10.4049/jimmunol.1402736. Epub 2015 May 13.

DOI:10.4049/jimmunol.1402736
PMID:25972485
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4458437/
Abstract

Polymorphisms in the B lymphoid tyrosine kinase (BLK) gene have been associated with autoimmune diseases, including systemic lupus erythematosus, with risk correlating with reduced expression of BLK. How reduced expression of BLK causes autoimmunity is unknown. Using Blk(+/+) , Blk(+/-) , and Blk(-/-) mice, we show that aged female Blk(+/-) and Blk(-/-) mice produced higher anti-dsDNA IgG Abs and developed immune complex-mediated glomerulonephritis, compared with Blk(+/+) mice. Starting at young age, Blk(+/-) and Blk(-/-) mice accumulated increased numbers of splenic B1a cells, which differentiated into class-switched CD138(+) IgG-secreting B1a cells. Increased infiltration of B1a-like cells into the kidneys was also observed in aged Blk(+/-) and Blk(-/-) mice. In humans, we found that healthy individuals had BLK genotype-dependent levels of anti-dsDNA IgG Abs as well as increased numbers of a B1-like cell population, CD19(+)CD3(-)CD20(+)CD43(+)CD27(+), in peripheral blood. Furthermore, we describe the presence of B1-like cells in the tubulointerstitial space of human lupus kidney biopsies. Taken together, our study reveals a previously unappreciated role of reduced BLK expression on extraperitoneal accumulation of B1a cells in mice, as well as the presence of IgG autoantibodies and B1-like cells in humans.

摘要

B淋巴细胞酪氨酸激酶（BLK）基因的多态性与自身免疫性疾病相关，包括系统性红斑狼疮，风险与BLK表达降低相关。BLK表达降低如何导致自身免疫尚不清楚。利用Blk(+/+)、Blk(+/-)和Blk(-/-)小鼠，我们发现与Blk(+/+)小鼠相比，老年雌性Blk(+/-)和Blk(-/-)小鼠产生更高水平的抗双链DNA IgG抗体，并发生免疫复合物介导的肾小球肾炎。从幼年开始，Blk(+/-)和Blk(-/-)小鼠脾脏B1a细胞数量增加，这些细胞分化为类别转换的分泌CD138(+) IgG的B1a细胞。在老年Blk(+/-)和Blk(-/-)小鼠中也观察到B1a样细胞向肾脏的浸润增加。在人类中，我们发现健康个体的抗双链DNA IgG抗体水平存在BLK基因型依赖性，外周血中B1样细胞群体CD19(+)CD3(-)CD20(+)CD43(+)CD27(+)的数量也增加。此外，我们描述了人类狼疮肾活检组织肾小管间质空间中存在B1样细胞。综上所述，我们的研究揭示了BLK表达降低在小鼠腹膜外B1a细胞积累方面以前未被认识到的作用，以及人类中IgG自身抗体和B1样细胞的存在。