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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 …