In This Issue Free

Bruton’s tyrosine kinase (BTK) is a member of the Tec family of tyrosine kinases and is critical for both BCR and Fc receptor signaling. Autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), are linked to aberrant B cell responses. In this issue, Haselmayer et al. (p. 2888) show that pharmacological inhibition of BTK attenuated B cell–driven autoimmune diseases. They characterized a specific and irreversible BTK inhibitor, evobrutinib, which bound covalently to BTK and inhibited BCR and Fc receptor signaling. Evobrutinib treatment was associated with reduced RA progression and joint damage in a collagen-induced arthritis model. In an IFN-α–accelerated NZB/W F1 lupus model, evobrutinib reduced B cell activation, autoantibody production, and the severity of lupus-associated kidney damage. Pharmacokinetic/pharmacodynamic modeling indicated that almost complete protection against RA or SLE disease manifestations was associated with 80% inhibition of BTK. These results characterize evobrutinib as a specific, irreversible BTK inhibitor with efficacy in both murine RA and SLE models and suggest that it may also be effective in treating other BTK-driven immune pathologies.

B cell chronic lymphocytic leukemia (B-CLL) is a hematologic malignancy characterized by a gradual increase in CD5⁺ B cells. Recent studies suggest that IL-15 may be critical in driving B-CLL growth. In this issue, Gupta et al. (p. 2924) examine the mechanism by which IL-15 drives B-CLL proliferation. They used CpG oligodeoxynucleotide (ODN)-primed B-CLL cells treated with IL-15 to characterize signaling events associated with B-CLL cycling. The authors observed that both PI3K/AKT and STAT5 pathways were involved in IL-15–driven growth. These signaling pathways promoted elevated expression of cyclin D2 and reduced expression of the DNA damage response mediators ATM, 53PB1, and MDC1. Interestingly, B-CLL cycling was dramatically reduced by pharmacological inhibition of PI3K or STAT5 in B-CLL cells treated with ODN and IL-15. These results clarify the role of IL-15 in B-CLL proliferation and point to potential new therapeutic avenues that target this cytokine signaling pathway.

Serotonin, also known as 5-hydroxytryptamine (5-HT), is produced primarily by enterochromaffin (EC) cells in the gut mucosa and is critical for modulating a number of physiological processes in the gut. In this issue, Wang et al. (p. 3041) identify a role for TLR 2 in 5-HT production. Naive mice treated with antibiotics exhibited significantly decreased levels of colonic 5-HT and 5-HT–expressing EC cells relative to untreated controls, and this corresponded to significantly lower expression of TLR2 by EC cells. Further investigation revealed that Tlr2^−/− mice had lower 5-HT levels in EC cells and fecal samples, and reconstitution of TLR2 expression in the hematopoietic compartment did not restore 5-HT production. In contrast, activation of TLR2 signaling upregulated expression of 5-HT and Tph1, the rate-limiting enzyme involved in 5-HT synthesis, in both murine and human EC cells. In addition, TLR2-driven production of 5-HT protected mice against infection with the enteric parasite Trichuris muris. Together, these results define a role for TLR2 signaling in 5-HT production and provide insight into how this pathway may be exploited for the treatment of gut disorders.

Flow cytometric methods incorporate polystyrene beads as an experimental tool in multiple ways, including calibration, cell counting, phagocytosis assays, and more. These beads, however, are not useful in mass cytometry. In this issue, Budzinski et al. (p. 3103) demonstrate that commercially available polystyrene beads, from multiple vendors, can be converted into a useful mass cytometry tool via labeling with osmium tetroxide (OsO₄). Os labeling of polystyrene beads did not impede their binding to various metal–Ab conjugates. The authors showed that Os-labeled beads could be combined with cell sample joint acquisition to facilitate mass cytometer compensation. Finally, blood from systemic lupus erythematosus patients was analyzed to confirm that Os-labeled beads, along with Ab binding capacity, can be used in high-dimensional immune phenotyping studies. These data provide a method by which commercially available polystyrene beads can be used to standardize receptor expression data in mass cytometry, thereby increasing their utility in biomedical research.