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 2

CD6 and ALCAM are overexpressed in renal tissue of patients with LN.

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CD6 and ALCAM are overexpressed in renal tissue of patients with LN. A s...
A single-cell RNA-Seq data set derived from epithelial cells and leukocytes isolated from the kidney biopsies of 24 patients with LN and 9 control subjects and urine cells collected from patients with LN only was analyzed for CD6 and ALCAM expression. Cells from the patients of each respective disease state were combined for analysis. (A) Box and whisker plots representing 25th, 50th, and 75th percentiles ± min/max of the number of cells with detectable CD6 expression (left panel) and ALCAM expression (right panel) in LN and control. UD = undetected. Comparisons between groups performed by Mann-Whitney U test. **P < 0.01 for CD6 expression on K. leukocytes. (B) Single-cell expression levels of CD6 and ALCAM. (C) Violin plots depicting expression of CD6 (left panel) and ALCAM (right panel) within specific renal cell populations of patients with LN. Expression of CD6 is primarily elevated in T cells and expression of ALCAM is elevated in epithelial cells isolated from renal tissue of LN subjects. (D) Violin plots of coexpression of CD6 with markers of CD4, CD8, and T helper subsets, Th1 (TBX21), Th2 (GATA3), and Th17 (RORC) subsets.