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.

Exploring urine:serum fractional excretion ratios as potential biomarkers for lupus nephritis

“…ALCAM FE also revealed strong positive correlation with renal-SLEDAI and good correlation with SLEDAI, anti-dsDNA and PGA, as well as an association with higher renal pathology AI. This finding is in line with recent studies ( 8 , 20 – 22 ) where urinary ALCAM was increased in active LN patients especially those with proliferative LN. ALCAM (CD166) is a glycoprotein and adhesion molecule of the immunoglobulin superfamily that is involved in T-cell co-stimulation, cell adhesion, angiogenesis, monocyte transmigration, and leukocyte intravasation into tissues ( 20 , 23 – 26 ).…”

Urine ALCAM, PF4 and VCAM-1 Surpass Conventional Metrics in Identifying Nephritis Disease Activity in Childhood-Onset Systemic Lupus Erythematosus

“…Additional studies in aSLE cohorts provide further support for these proteins, endorsing their role as biomarkers for early detection of LN flare-ups and as potential therapeutic targets in LN. These include studies focusing on these biomarkers highlighting their potential utility in serial biomarker tracking, predicting clinical and pathological activity in LN, and biomarker-directed therapeutic targeting (50)(51)(52).…”

Gene Variation at Immunomodulatory and Cell Adhesion Molecules Loci Impacts Primary Sjögren's Syndrome

“…From the functional point of view, CD5 and CD6 are considered relevant signaling immune receptors at the interphase of the innate and adaptive immune responses as a result from their involvement in (i) the recognition and sensing of bacterial, viral, and/or parasitic MAMPs ( 17) and (ii) the fine-tuning of lymphocyte activation signals delivered by clonotypic T and B antigen-specific receptors, which they are physically associated to (58)(59)(60). While the nature of the endogenous CD5 ligand is yet uncertain, one of the most-well studied CD6 ligands is CD166/ALCAM, a cell adhesion molecule overexpressed in pSS salivary gland epithelial cells (8,9,25), but also RA synovium (61), MS blood-brain barrier endothelium (62), and lupus nephritis kidneys (63), thus contributing to T and B cell migration and infiltration at inflamed tissues in autoimmune processes. Second, several CD5, CD6, and/or CD166/ALCAM gene variants have been associated with different IMIDs, such as RA (38), lupus nephritis (39), MS (40)(41)(42), psoriasis (43), Behçet's disease (44), and IBD (45,46) (Supplementary Table 2).…”