The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.
The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.
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DOI：
10.1172/jci147334
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发表时间：
2022-01-04
期刊：
影响因子：
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通讯作者：
Putterman C
中科院分区：
文献类型：
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作者：
Chalmers SA;Ayilam Ramachandran R;Garcia SJ;Der E;Herlitz L;Ampudia J;Chu D;Jordan N;Zhang T;Parodis I;Gunnarsson I;Ding H;Shen N;Petri M;Mok CC;Saxena R;Polu KR;Connelly S;Ng CT;Mohan C;Putterman C
狼疮肾炎（LN）是系统性红斑狼疮（SLE）的常见并发症，T细胞在狼疮肾炎（LN）的发病机制中起着核心作用。CD6及其配体活化白细胞粘附分子（activated leukocyte cell adhesion molecule， ALCAM）参与T细胞的活化和转运。先前，我们发现LN患者尿液中可溶性ALCAM （uALCAM）增加，表明该途径与疾病有关。为了进行调查，研究人员对来自5个不同种族的1038例SLE和LN患者进行了uALCAM检查；检测LN肾细胞中CD6和ALCAM的表达；通过抗体阻断CD6在SLE和急性肾小球肾炎小鼠模型中检测疾病贡献。扩展队列分析有力地验证了uALCAM作为区分SLE活动性肾脏受累的生物标志物的有效性，无论种族如何。ALCAM在肾结构细胞中表达，而CD6仅在T细胞中表达，在LN患者中CD6+和ALCAM+细胞数量升高。CD6阻断在自发性狼疮和免疫复合物肾小球肾炎模型中显示免疫细胞、炎症标志物和疾病指标显著降低。我们的数据证明了CD6/ALCAM通路对LN和SLE的贡献，支持其作为疾病生物标志物和治疗靶点的使用。
T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.