Background/Purpose: B cell depletion therapy with anti-CD20 antibody rituximab has emerged as a potential treatment for systemic sclerosis (SSc). Rituximab, which has been used to treat B cell malignancies and some autoimmune diseases, efficiently depletes circulating B cells. Tissue-resident B cells, on the other hand, have been shown to be more difficult to deplete, posing a therapeutic challenge. Resistance of tissue-resident B cells to rituximab has been associated with the inflammatory microenvironment in malignancy and autoimmunity, where B cell survival is promoted by various cytokines and chemokines. Among these survival factors, the following two have received much attention: CXCL12, a chemokine essential for the B cell niche in bone marrow, and B cell activating factor (BAFF), a cytokine promoting the survival of autoreactive B cells. In this study, we investigated the role of microenvironment on tissue-resident B cells during B cell depletion therapy with anti-CD20 antibody in SSc.

Methods: Bleomycin (BLM)-induced SSc model mice were treated with anti-CD20 antibody. AMD 3100, an antagonist of the CXCL12 receptor CXCR4, was used to block CXCL12. Anti-BAFF antibody was used to block BAFF. B cell depletion was assessed by flow cytometry in bone marrow, spleen, lymph nodes, lungs, and peripheral blood. Skin and lung fibrosis was evaluated histopathologically. CXCL12 and BAFF expression was quantified by qRT-PCR and immunofluorescence staining.

Results: While anti-CD20 antibody efficiently depleted circulating B cells and attenuated skin and lung fibrosis, a fraction of CD20⁺ B cells persisted in spleen, lymph nodes, and lungs of BLM-induced SSc model mice, contrasting with efficient depletion of tissue-resident B cells in control mice. Residual B cells showed increased expression of CXCR4. CXCL12 and BAFF expression was increased in skin and lungs of BLM-induced SSc model mice. Co-administration of anti-CD20 antibody with AMD3100 or anti-BAFF antibody enhanced the depletion of tissue-resident B cells. Furthermore, these combination therapies achieved greater attenuation of fibrosis in BLM-induced SSc model mice compared with anti-CD20 monotherapy.

Conclusion: SSc microenvironment provides a protective niche for tissue-resident B cells against anti-CD20 antibody. B cell survival factors like CXCL12 and BAFF are potential therapeutic targets that enhance the efficacy of B cell depletion therapy in SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/microenvironment-in-systemic-sclerosis-provides-a-protective-niche-for-tissue-resident-b-cells-during-b-cell-depletion-therapy-with-anti-cd20-antibody/