B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the δ isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110δ enzymatic activity, we show that p110δ is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110δ activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110δ activity. Finally, we show that the in vivo production of natural Abs requires p110δ and that p110δ inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110δ may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.

Objective.To summarize patients’ preferences for disease-modifying antirheumatic drug (DMARD) therapy in rheumatoid arthritis (RA).Methods.We conducted a systematic review to identify English-language studies of adult patients with RA that measured patients’ preferences for DMARD or health states and treatment outcomes relevant to DMARD decisions. Study quality was assessed using a published quality assessment tool. Data on the importance of treatment attributes and associations with patient characteristics were summarized across studies.Results.From 7951 abstracts, we included 36 studies from a variety of countries. Most studies were in patients with established RA and were rated as medium- (n = 19) or high-quality (n = 12). The methods to elicit preferences varied, with the most common being discrete choice experiment (DCE; n = 13). Despite the heterogeneity of attributes in DCE studies, treatment benefits (disease improvement) were usually more important than both non-serious (6 of 8 studies) and serious adverse events (5 of 8), and route of administration (7 of 9). Among the non-DCE studies, some found that patients placed high importance on treatment benefits, while others (in patients with established RA) found that patients were quite risk averse. Subcutaneous therapy was often but not always preferred over intravenous therapy. Patient preferences were variable and commonly associated with the sociodemographic characteristics.Conclusion.Overall, the results showed that many patients place a high value on treatment benefits over other treatment attributes, including serious or minor side effects, cost, or route of administration. The variability in patient preferences highlights the need to individualize treatment choices in RA.