TY - JOUR
T1 - The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses
AU - Chalmers, Samantha A.
AU - Ramachandran, Rajalakshmy Ayilam
AU - Garcia, Sayra J.
AU - Der, Evan
AU - Herlitz, Leal
AU - Ampudia, Jeanette
AU - Chu, Dalena
AU - Jordan, Nicole
AU - Zhang, Ting
AU - Parodis, Ioannis
AU - Gunnarsson, Iva
AU - Ding, Huihua
AU - Shen, Nan
AU - Petri, Michelle
AU - Mok, Chi Chiu
AU - Saxena, Ramesh
AU - Polu, Krishna R.
AU - Connelly, Stephen
AU - Ng, Cherie T.
AU - Mohan, Chandra
AU - Putterman, Chaim
N1 - Funding Information:
This work was supported in part by funding from the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public-private partnership created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was also provided through grants from the National Institutes of Health (UH2‑AR067676, UH2‑AR067677, UH2‑AR067679, UH2-AR067681, UH2‑AR067685, UH2‑AR067688, UH2‑AR067689, UH2‑AR067690, UH2‑AR067691, UH2‑AR067694, and UM2-AR067678); the Lupus Research Alliance and the NIH (AR NIH R01 AR074096 to CM); the NIH (R01‑AR069572 and UH2AR067679 to MP); the George M. O’Brien Kidney Research Core Center (NIH grant P30DK079328 to RS); and the Swedish Rheumatism Association (R‑932236), the King Gustaf V’s 80-year Foundation (FAI‑2019‑0635), the Professor Nanna Svartz Foundation (2019-00290), the Ulla and Roland Gustafsson Foundation (2019‑12), Region Stockholm, and Karolinska Institute (all to IP).
Publisher Copyright:
Copyright: © 2022, Chalmers et al.
PY - 2022/1/4
Y1 - 2022/1/4
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI147334
DO - 10.1172/JCI147334
M3 - Article
C2 - 34981775
AN - SCOPUS:85122827017
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - e147334
ER -