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 9

Blockade of CD6 decreases expression of inflammatory cytokines/chemokines.

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Blockade of CD6 decreases expression of inflammatory cytokines/chemokine...
NTN was induced in female 129/SvJ mice at 10 weeks of age. Mice were immunized with rabbit IgG and CFA on day 0 to generate mouse anti–rabbit antibodies. At day 5, mice received nephrotoxic rabbit serum, which then cross-reacted with the mouse anti–rabbit antibodies, causing an antibody-mediated nephritis. Beginning day 4, mice were treated 3 times per week with anti–mouse CD6 (60 μg/dose; n = 12), vehicle control (n = 12), or isotype control (n = 5). Healthy mice (immunized with rabbit IgG, but not given nephrotoxic serum) were also included as a nondisease control (n = 6). At day 11 to 12, mice were sacrificed and kidneys were harvested to analyze RNA and protein levels of inflammatory markers. (A) Volcano plot of results of PCR array examining expression of 86 genes associated with inflammation in RNA isolated from kidneys of anti-CD6– and isotype-treated mice. (B) Heat map of genes that differed by more than 3-fold between isotype- and anti-CD6–treated mice. (C) Protein levels of select genes (IL-23, IFN-γ, IL-12p70, and IL-17) in renal tissue, as quantitated by flow-based ELISA. Data represent mean ± SE. Comparisons between groups were evaluated using 1-way ANOVA with multiple-comparisons test. **P < 0.01; *P < 0.05.