The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses
Samantha A. Chalmers, … , Chandra Mohan, Chaim Putterman
Samantha A. Chalmers, … , Chandra Mohan, Chaim Putterman
Published January 4, 2022
Citation Information: J Clin Invest. 2022;132(1):e147334. https://doi.org/10.1172/JCI147334.
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Research Article Autoimmunity

The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses

Abstract

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.

Authors

Samantha A. Chalmers, Rajalakshmy Ayilam Ramachandran, Sayra J. Garcia, Evan Der, Leal Herlitz, Jeanette Ampudia, Dalena Chu, Nicole Jordan, Ting Zhang, Ioannis Parodis, Iva Gunnarsson, Huihua Ding, Nan Shen, Michelle Petri, Chi Chiu Mok, Ramesh Saxena, Krishna R. Polu, Stephen Connelly, Cherie T. Ng, Chandra Mohan, Chaim Putterman

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Figure 6

Anti-CD6 treatment inhibits renal pathology in the MRL/lpr model of SLE.

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Anti-CD6 treatment inhibits renal pathology in the MRL/lpr model of SLE....
Female MRL/lpr mice at 9 to 10 weeks of age were treated with either anti-CD6 monoclonal antibody (60 μg/dose, i.p. twice per week, n = 12), isotype control (60 μg/dose, i.p. twice per week, n = 12), cyclophosphamide (25 mg/kg, once per week, n = 12), or mycophenolate mofetil (MMF; 50 mg/kg, oral gavage daily, n = 12). A group of MRL/MpJ mice (n = 6), a congenic control strain, were included in the study. (A) Images of H&E sections from kidney of treated MRL/lpr and MPJ control mice. Magnification is 400×. (B) Pathology scores of H&E sections as scored by a blinded pathologist. Glomerular scores were assigned based on crescents, endocapillary hypercellularity, and immune material deposition while tubular scores were assigned based on casts/dilatation and interstitial inflammation. Scoring data are presented as box and whisker plots representing 25th, 50th, and 75th percentiles ± min/max. (C) Kidney weight at termination. Inflammation results in increased tissue weight. (D) Detection of CD4, B220, and IBA1 in immunofluorescently stained kidney sections. Data are presented as mean ± SE. All data represent 2 independent experiments. Comparisons between groups were evaluated using 1-way ANOVA with multiple-comparisons test against the isotype group. ***P < 0.001; **P < 0.01; *P < 0.05 versus isotype.