Transgenic expression of TLR7 results in the expansion and hyperactivation of T1 B cells in response to endogenous RNA complexes, leading to increased autoantibody production.

Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)–driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6Chi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)–like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.

This study demonstrates that X6 is superior to HCQ for the treatment of an experimental autoimmune myocarditis mediated in vivo by the cGAS/stimulator of IFN genes (cGAS/STING) pathway. The findings suggest that drug X6 could be developed as a novel treatment for AGS and/or lupus to inhibit activation of the cGAS/STING pathway.

T helper-2 (T H 2)-bias, the propensity of naive CD4 + T cells to differentiate into interleukin 4 (IL-4) secreting T H 2 cells, is a genetic trait impacting infectious, autoimmune and allergic disease susceptibility. T H 2-bias correlates with the amount of IL-4 initially secreted by newly activated T H cells that feeds back positively through the IL-4R-STAT6-GATA3 pathway to drive T H 2 development. Here, we identify Mina, a JmjC family member, as a genetic determinant of T H 2-bias. Mina specifically bound to and repressed the Il4 promoter. Mina overexpression in transgenic mice impaired Il4 expression, while its knockdown in primary CD4 + T cells led to Il4 derepression. Together, these findings provide mechanistic insight into an Il4 regulatory pathway controlling T H differentiation and genetic variation in T H 2-bias. Naive CD4 + T cells are multipotent sentinels of the immune system, poised to respond to instructive signals from antigen-presenting cells by differentiating into distinct effector cell lineages. These include T helper (T H ) 1 and T H 2 cells, differentially adapted for the control, respectively, of intra-and extracellular pathogens, in part via developmentally acquired potential for high expression of distinct cytokine genes 1 . Dysregulated CD4 + T cell development can promote susceptibility to infectious, autoimmune and allergic disease [2][3][4][5][6][7][8][9] .Interleukin 4 (IL-4) [http://www.signaling-gateway.org/molecule/query?afcsid=A001262], the canonical T H 2 effector cytokine, is also a critical developmental determinant, promoting Accession codesThe microarray data are deposited in RCAI RefDIC (URL: http://refdic.rcai.riken.jp/welcome.cgi) 50 under the following accession codes: RMSPTB007001 and RMSPTB008001. 11,12 to promote the differentiation of T H 2 cells possessing the capacity to secrete copious amounts of IL-4 10, 13-18 . Thus, regulation of autocrine IL-4 expression by activated T H cells is a key control point in T helper cell lineage commitment. Nonetheless, the molecular mechanism underlying this regulation is incompletely understood. Author contributions NIH Public AccessT H 2-bias is a complex genetic trait characterizing variation in the propensity of naive T H cells to differentiate into T H 2 (as opposed to T H 1) cells. T H 2-bias, measured experimentally as the amount of IL-4 produced by effector CD4 + T cells differentiated in vitro from naive T H cells activated under 'neutral' conditions (no exogenous cytokines added, except IL-2, and cultured without cytokine-specific antibodies), varies over 50-fold from the highproducer phenotype of BALB/c mice to the low-producer phenotype of B10.D2 mice and correlates with susceptibility to T H 2-dependent diseases such as bronchial asthma and leishmaniasis [14][15][16][19][20][21][22] . Various cellular mechanisms have been suggested as the basis for T H 2-bias, including variation in the sensitivity to prostaglandin 2 (PGE 2 )-dependent inhibition of interferon-γ (IFN-γ) production 23 , the timing of IL-1...