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.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that predominantly affects women in the reproductive age range
Soluble urinary ALCAM (uALCAM) correlates with disease severity in patients with lupus nephritis (LN)
Assessment of the alternate CD6 ligand, CD318, showed urine levels that were below detection while serum levels did not distinguish between patients with active LN versus patients with active, nonrenal disease or inactive SLE (Supplemental Figure 2A)
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that predominantly affects women in the reproductive age range. Though the precise etiology of SLE is not well understood, the disease is broadly characterized by immune dysregulation, including aberrant T and B cell activity [2]. Multiple CD4+ T helper (Th) cell subsets, including Th1, Th2, and Th17 and their associated cytokines, as well as cytotoxic CD8+ T cells, have all been implicated in the immune pathogenesis of both SLE and LN, highlighting the complex nature of the disease. High levels of IL‐17 predict poor histopathological outcome after immunosuppressive therapy in patients with LN [3, 5, 6], while elevated levels of Th17 cells are accompanied by a decrease in Tregs, suggesting that loss of functional immune balance may be involved in the pathogenesis of renal injury in patients with SLE [6]
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