ALCAM Deficiency Dampens Renal Inflammation in Lupus Nephritis



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Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease affecting many organs. In nearly 50% of patients with SLE, the disease progresses to lupus nephritis (LN), a severe complication of SLE that increases the risk of end-stage kidney disease and mortality. There is no cure for LN, and the pathogenesis of the disease remains incompletely understood. In a comprehensive screening of over 1000 urine proteins, the activated leukocyte cell adhesion molecule (ALCAM) was identified as a top molecule elevated in the urine of patients with active LN compared to healthy controls. Expressed on antigen presenting cells, ALCAM serves as CD6 ligand. ALCAM binds CD6, resulting in recruitment of signaling factors such as SLP-76 and GADs that enhance TCR signaling. It also activates several MAPK pathways related to T cell activation, proliferation, differentiation, and infiltration into inflamed renal tissues. Such upregulated T cell activity contributes to end organ disease by promoting autoantibody production, subsequently leading to B cell differentiation and expansion. Despite its significant modulation of immunity, the precise role of ALCAM in the development of LN remains unknown. Given ALCAM's published function in autoimmunity, we examined whether the development of LN is contingent upon the presence of ALCAM. We anticipate that our study will shed light on ALCAM's role as a key pathogenic player and potential therapeutic agent in lupus nephritis.