Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy

• Published in: Science translational medicine 2015-10, Vol.7 (310), p.310ra166-310ra166
• Main Authors: Li, Rui, Rezk, Ayman, Miyazaki, Yusei, Hilgenberg, Ellen, Touil, Hanane, Shen, Ping, Moore, Craig S, Michel, Laure, Althekair, Faisal, Rajasekharan, Sathy, Gommerman, Jennifer L, Prat, Alexandre, Fillatreau, Simon, Bar-Or, Amit
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - chemistry; B-Lymphocytes - metabolism; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Humans; Inflammation Mediators - metabolism; Lymphocyte Depletion; Multiple Sclerosis - pathology
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aab4176

B cells are not limited to producing protective antibodies; they also perform additional functions relevant to both health and disease. However, the relative contribution of functionally distinct B cell subsets in human disease, the signals that regulate the balance between such subsets, and which of these subsets underlie the benefits of B cell depletion therapy (BCDT) are only partially elucidated. We describe a proinflammatory, granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing human memory B cell subset that is increased in frequency and more readily induced in multiple sclerosis (MS) patients compared to healthy controls. In vitro, GM-CSF-expressing B cells efficiently activated myeloid cells in a GM-CSF-dependent manner, and in vivo, BCDT resulted in a GM-CSF-dependent decrease in proinflammatory myeloid responses of MS patients. A signal transducer and activator of transcription 5 (STAT5)- and STAT6-dependent mechanism was required for B cell GM-CSF production and reciprocally regulated the generation of regulatory IL-10-expressing B cells. STAT5/6 signaling was enhanced in B cells of untreated MS patients compared with healthy controls, and B cells reemerging in patients after BCDT normalized their STAT5/6 signaling as well as their GM-CSF/IL-10 cytokine secretion ratios. The diminished proinflammatory myeloid cell responses observed after BCDT persisted even as new B cells reconstituted. These data implicate a proinflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases.