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

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

doi:10.1172/JCI147334

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

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 MohanChaim Putterman

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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.

Original language	English
Article number	e147334
Journal	Journal of Clinical Investigation
Volume	132
Issue number	1
DOIs	https://doi.org/10.1172/JCI147334
State	Published - 4 Jan 2022

Bibliographical note

Publisher Copyright:
Copyright: © 2022, Chalmers et al.

Funding

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).

Funders	Funder number
George M. O’Brien Kidney Research Core Center	P30DK079328
Professor Nanna Svartz Foundation	2019-00290
Ulla and Roland Gustafsson Foundation	2019‑12
National Institutes of Health	UH2‑AR067677, UH2‑AR067689, UH2‑AR067679, UM2-AR067678, UH2‑AR067690, UH2‑AR067691, UH2-AR067681, UH2‑AR067694, UH2‑AR067685, UH2‑AR067676
National Institute of Arthritis and Musculoskeletal and Skin Diseases	UH2AR067688
Lupus Research Alliance	AR NIH R01 AR074096, R01‑AR069572, UH2AR067679
Karolinska Institutet
Stiftelsen Konung Gustaf V:s 80-årsfond	FAI‑2019‑0635
Reumatikerförbundet	R‑932236

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Chalmers, S. A., Ramachandran, R. A., Garcia, S. J., Der, E., Herlitz, L., Ampudia, J., Chu, D., Jordan, N., Zhang, T., Parodis, I., Gunnarsson, I., Ding, H., Shen, N., Petri, M., Mok, C. C., Saxena, R., Polu, K. R., Connelly, S., Ng, C. T., ... Putterman, C. (2022). The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses. Journal of Clinical Investigation, 132(1), Article e147334. https://doi.org/10.1172/JCI147334

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title = "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.",

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

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Chalmers, SA, Ramachandran, RA, Garcia, SJ, Der, E, Herlitz, L, Ampudia, J, Chu, D, Jordan, N, Zhang, T, Parodis, I, Gunnarsson, I, Ding, H, Shen, N, Petri, M, Mok, CC, Saxena, R, Polu, KR, Connelly, S, Ng, CT, Mohan, C & Putterman, C 2022, 'The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses', Journal of Clinical Investigation, vol. 132, no. 1, e147334. https://doi.org/10.1172/JCI147334

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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

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

Abstract

Bibliographical note

Funding

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