Bad B cells make GM-CSF

Li et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy.Sci Transl Med. 2015 Oct 21;7:310ra166.

Background: 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 pro-inflammatory 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.

Immunology is complex and gets more complex as more discoveries occur. We know that the B cell is where the action is. With the exception of daclizumab all highly effective DMTs have an effect on B cells. The fact that targeting mainly B cells with anti-CD20 therapy has proven to be very effective is proof that the B cell is likely to be the main target of these therapies.  This is associated with the loss of B cell population that makes a cytkine called GM-CSF which controls a B regulatory cell that produces interleukin 10. So we have pathogenic and regulatory B cells will they replace pathogenic and regulatory B cells

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