Background/Purpose: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of several organs. SSc-associated interstitial lung disease (ILD) is a frequent and severe complication of SSc. SSc-ILD declines the quality of patients’ lives and sometimes determines their prognosis. Despite the severeness of SSc-ILD, the treatment for SSc-ILD is still debated. The cyclophosphamide (CYC) treatment is the only therapy found to be effective in stabilizing or improving lung function of SSc-ILD in randomized clinical trials, which contained abundant numbers of patients. However, not every SSc-ILD patients treated with CYC recover. We need to know the difference between the responders and the non-responders against CYC. Recent studies indicate that B cells play a critical role in SSc through their function of cytokine production. Indeed, some studies have reported that the B cell depletion therapy with rituximab can be effective for SSc-ILD. However, the relationship between response to CYC therapy and B cell function remains unknown in SSc-ILD. We hypothesized that cytokine-producing effector B cells determine the effectiveness of the CYC treatment in SSc-ILD patients. In this study, we assessed the role of interleukin (IL)-10-producing regulatory B cells and IL-6-producing pathogenic B cells in the responders or non-responders of the CYC treatment.

Methods: We cultured human lung endothelial cells (LECs) in a microchannel. Sequentially, B cells from responders or non-responders against the CYC treatment were loaded into the microchannel. After each of B cells which adhered to LECs had produced cytokines, we measured IL-6 and IL-10 production from single B cells by our original micro fluidic-ELISA system. Similarly, we assessed B cells from topoisomerase (topo) I and complete Freund’s adjuvant-induced SSc model mice.

Results: In SSc-ILD patients, the number of B cells adhering to LECs significantly increased relative to healthy controls. B cells adhering to LECs from CYC-responders produced significantly higher amounts of IL-10 and lower amounts of IL-6 than those from CYC-non-responders. After the CYC treatment, the frequency of B cells which adhered to LECs significantly decreased in responders but did not decrease in non-responders. Regarding the cytokine profile of B cells adhering to LECs, the frequencies of IL-10 producing regulatory B cells after the CYC treatment increased in responders and decreased in non-responders. Those of IL-6-producing pathogenic B cells after the CYC treatment decreased in responders and increased in non-responders. In the mouse study, the number of topo I-specific B cells which adhere to LECs significantly increased compared to non-specific conventional B cells. Topo I-specific B cells also showed significantly higher production of IL-6 and lower production of IL-10 than conventional B cells.

Conclusion: These results suggested that the effectiveness of CYC to SSc-ILD patients is associated with the cytokine profile of B cells which interact with LECs. It is likely that IL-6-producing pathogenic B cells which survived the CYC treatment damage the lung function of non-responders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/single-cell-analysis-revealed-that-the-response-to-cyclophosphamide-therapy-is-regulated-by-b-cells-in-systemic-sclerosis-associated-interstitial-lung-disease/