Aberrant sphingosine-1-phosphate receptor 1 expression on activated naive B cells associated with disease activity and lupus nephritis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by the immune system producing autoantibodies that target the body's own cells and tissues, leading to inflammation and tissue damage. Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in regulating immune cell trafficking, and its function relies on a gradient of sphingosine-1-phosphate (S1P). During inflammatory immune responses, the S1P gradient is altered, promoting lymphocyte migration to inflammatory sites. Consequently, S1PR1 has become a therapeutic target for inhibiting lymphocyte egress from lymphoid tissues in autoimmune and inflammatory diseases. However, knowledge of S1PR1 expression and function in B cell subsets and antibody-secreting cells (ASCs) in SLE remains limited.

Peripheral blood mononuclear cells (PBMCs) from forty-nine patients with SLE were enrolled to assess S1PR1 expression in B cell subsets and plasma cells. Significant differences in surface S1PR1 expression on activated naive (aNAV), Double Negative 2 (DN2) B cells and ASCs were further analyzed for correlations with disease activity, Lupus Nephritis (LN) involvement, inflammatory markers, S1P levels, and chemokine receptor expression.

Intracellular S1PR1 expression was significantly increased across all B cell subsets, including naive (rNAV and aNAV), memory (SWM, USM, DN1, DN2), and ASCs. In contrast, surface S1PR1 expression differed markedly among subsets, with downregulation observed in aNAV and DN2 B cells and upregulation in ASCs. Further analysis revealed that surface S1PR1 downregulation on aNAV B cells was significantly associated with active disease status, SLEDAI-2 K scores, and LN involvement. Inflammatory markers (IL-6, IL-8, and C3c levels) showed no correlation with surface S1PR1 expression, whereas erythrocyte sedimentation rate (ESR) demonstrated a significant negative correlation. In addition, lupus aNAV and DN2 B cells exhibited reduced surface CXCR3 expression without correlation to S1PR1 expression, whereas other B cell subsets in SLE subjects showed a significant correlation between CXCR3 and S1PR1 expression.

Surface S1PR1 expression was downregulated in aNAV and DN2 B cells. Clinically, decreased surface S1PR1 expression on aNAV B cells was significantly correlated with active status, increased disease activity, LN involvement, and elevated ESR. The increased S1P levels, along with S1PR1 and CXCR3 downregulation, suggest that chronic activation characteristic of SLE may drive S1PR1 desensitization or internalization in aNAV B cells, thereby altering their ability to dynamically recirculate or respond to inflammation-associated signal target tissues.