Journal Article

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

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

2022

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: African Americans / Animal models / Animals / Antigens, CD - immunology / Antigens, Differentiation, T-Lymphocyte - immunology / Autoimmunity / Biomarkers / Biomedical research / Care and treatment / CD6 antigen / Cell activation / Cell adhesion & migration / Cell adhesion molecules / Cell Adhesion Molecules, Neuronal - immunology / Complications and side effects / Creatinine / Cytokines / Datasets / Development and progression / Ethnicity / Female / Fetal Proteins - immunology / Genetic aspects / Glomerulonephritis / Health aspects / Humans / Immune response / Inflammatory diseases / Kidney - immunology / Kidney - pathology / Kidney diseases / Kidneys / Kinases / Ligands / Lupus / Lupus nephritis / Lupus Nephritis - immunology / Lupus Nephritis - pathology / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Mice / Minority & ethnic groups / Nephritis / Pathogenesis / Patients / Systemic lupus erythematosus / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Therapeutic targets / Urine