Date: Sunday, November 5, 2017
Session Title: B Cell Biology and Targets in Autoimmune Disease Poster
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic sclerosis (SSc) is a T helper type 2 (Th2)-driven autoimmune disease characterized by vasculopathy and fibrosis. There are still unmet needs in the management of SSc, however B-cell depletion therapy has recently been reported to be effective for this disease. Intriguingly here there is no significant correlation between autoantibody titers and the improvement of clinical symptoms, thus highlighting a novel antibody-independent function of B cells, particularly cytokine production, involved in the pathogenesis of SSc.Granulocyte-macrophage colony-stimulating factor (GM-CSF) exerts a wide range of biological effects mainly on myeloid cells, and B cells has recently been reported as another cellular source of GM-CSF that is induced by a Th2 cytokine IL-4. Given a pathological relevance of Th2 cytokines in SSc and association of GM-CSF with fibrotic processes in various rodent models, in the present study we have sought to elucidate a role of GM-CSF-producing B cells in this disease.
Methods: B cell subsets in peripheral blood from healthy donors and patients with SSc were enriched by cell sorting and subjected to the analysis of GM-CSF transcripts and proteins (intracellular staining and ELISA). The relationship between GM-CSF-producing B cells and the clinical features of SSc was also evaluated. To determine the functional impacts of GM-CSF-producing B cells on myeloid cells, B cells cultured under Th2 conditions were co-cultured with CD14+ monocytes.
Results: Among a panel of CD4+ T cell-derived cytokines, Th2 cytokine IL-4 most significantly induced the generation of GM-CSF-producing memory B cells, while T follicular helper (Tfh) cytokine IL-21 remarkably abrogated this process. Intriguingly TGF-b further potentiated IL-4-induced GM-CSF production in memory B cells. GM-CSF-producing effector B cells were positive for CD30, a distinct phenotype from Ab-producing cells induced by IL-21. GM-CSF production in B cells from patients with SSc was more pronounced than that from healthy donors. This trend was also observed in both naïve and memory B cell subsets. A subpopulation of SSc patients with the diffuse type and concomitant IP, in particular, represented enhanced GM-CSF production in memory B cells. Moreover, B cells cultured under Th2 conditions along with TGF-b facilitated the differentiation from CD14+ monocytes to DC-SIGN+CD1a+CD14-CD86+ cells, a novel DC subset previously reported in skin of SSc patients and SSc model mice.
Conclusion: Together, these findings suggest that GM-CSF-producing effector B cells is a novel B cell subset and play a critical role in the pathogenesis of SSc by Ab-independent mechanisms.
To cite this abstract in AMA style:Higashioka K, Ota Y, Nakayama T, Mishima K, Ayano M, Kimoto Y, Mitoma H, Akahoshi M, Arinobu Y, Akashi K, Horiuchi T, Niro H. GM-CSF-Producing B Cells: A Novel B Cell Subset Involved in the Pathogenesis of Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/gm-csf-producing-b-cells-a-novel-b-cell-subset-involved-in-the-pathogenesis-of-systemic-sclerosis/. Accessed February 26, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gm-csf-producing-b-cells-a-novel-b-cell-subset-involved-in-the-pathogenesis-of-systemic-sclerosis/