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 4

CD6 blockade improves survival and disease in MRL/lpr model of SLE.

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CD6 blockade improves survival and disease in MRL/lpr model of SLE. Fema...
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) Kaplan-Meier curve depicting survival by treatment group (n = 10–12 mice per group). (B) Lymphadenopathy as assessed by average of the weight of the left and right inguinal lymph nodes at termination. (C) Serum levels of anti-dsDNA autoantibodies as measured by ELISA. (D) Scoring of macroscopic skin lesions at termination (29 weeks). (E) Skin histopathology of treated MRL/lpr and MPJ control mice. Arrow points to hyperkeratosis, asterisks indicate damage of the dermal-epidermal junction, and black triangle points to large cellular infiltrates into the dermis. (F) Skin sections stained for IBA1 (green) to identify macrophages, C3 (red) to delineate complement, IgG (orange) to identify immune complexes, and DAPI (blue) to identify cell nuclei. Data are representative of 2 independent experiments. Bar graphs present mean ± SE. 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.