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Although individuals with coronavirus disease 2019 (COVID‐19) are known to be at increased risk for other conditions resulting from pathogenic changes (including metaplastic or anaplastic) in the lungs and other organs and organ systems, it is still unknown whether COVID‐19 affects childhood intelligence. The present two‐sample Mendelian randomization study aims to identify the genetic causal link between COVID‐19 and childhood intelligence. Four COVID‐19 genetic instrumental variants (IVs) were chosen from the largest genome‐wide association studies (GWAS) for COVID‐19 (hospitalized vs. population) (6406 cases and 902 088 controls of European ancestry). The largest childhood intelligence GWAS (n = 12 441 individuals of European ancestry) was used to evaluate the effect of the identified COVID‐19‐associated genetic IVs on childhood intelligence. We found that as the genetic susceptibility to COVID‐19 increased, childhood intelligence followed a decreasing trend, according to mr_egger (β = −0.156; p = 0.601; odds ratio [OR] = 0.856; 95% confidence interval [CI]: 0.522–1.405), simple mode (β = −0.126; p = 0.240; OR = 0.882; 95% CI: 0.745–1.044), and weighted mode (β = −0.121; p = 0.226; OR = 0.886; 95% CI: 0.758–1.036) analyses. This trend was further demonstrated by the weighted median (β = −0.134; p = 0.031; OR = 0.875; 95% CI: 0.774–0.988) and the inverse variance weighted (β = −0.152; p = 0.004; OR = 0.859; 95% CI: 0.776–0.952). Our analysis suggests a causal link between genetically increased COVID‐19 and decreased childhood intelligence. Thus, COVID‐19 may be a risk factor for declines in childhood intelligence. [ABSTRACT FROM AUTHOR]

T cell immunoglobulin and mucin domain‐3 (Tim‐3), an immune checkpoint molecule, plays critical roles in maintaining innate immune homeostasis; however, the mechanisms underlying these roles remain to be determined. Here, we determined that Tim‐3 controls glycolysis in macrophages and thus contributes to phenotype shifting. Tim‐3 signal blockade significantly increases lactate production by macrophages, but does not influence cell proliferation or apoptosis. Tim‐3 attenuates glucose uptake by inhibiting hexokinase 2 (HK2) expression in macrophages. Tim‐3‐mediated inhibition of macrophage glycolysis and the expression of proinflammatory cytokines, tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β are reversed by HK2 silencing. Finally, we demonstrated that Tim‐3 inhibits HK2 expression via the STAT1 pathway. We have thus discovered a new way by which Tim‐3 modulates macrophage function. [ABSTRACT FROM AUTHOR]

Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B‐cell‐specific Itch deficiency promoted antigen‐induced B‐cell activation and antibody‐expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19creItchf/f) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)‐like SP 2/0 cells, Itch deficiency promoted B‐cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen‐induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen‐driven B‐cell response. This may provide hints for Itch‐targeted treatment of patients with autoimmune disease. [ABSTRACT FROM AUTHOR]

The Nod-like receptor protein 3 ( NLRP3) inflammasome plays roles in host defence against invading pathogens and in the development of autoimmune damage. Strict regulation of these responses is important to avoid detrimental effects. Here, we demonstrate that T cell Ig mucin-3 (Tim-3), an immune checkpoint inhibitor, inhibits NLRP3 inflammasome activation by damping basal and lipopolysaccharide-induced nuclear factor- κB-mediated up-regulation of NLRP3 and interleukin-1 β during the priming step and basal and ATP/lipopolysaccharide-induced ATP production, K+ efflux, and reactive oxygen species production during the activation step. Residues Y256/Y263 in the C-terminal region of Tim-3 are required for these inhibitory effects on the NLRP3 inflammasome. In mice with alum-induced peritonitis, blockade of Tim-3 exacerbates peritonitis by overcoming the inhibitory effect of Tim-3 on NLRP3 inflammasome activation, while transgenic expression of Tim-3 attenuates inflammation by inhibiting NLRP3 inflammasome activation. Our results show that Tim-3 is a critical negative regulator of NLRP3 inflammasome and provides a potential target for intervention of diseases with uncontrolled inflammasome activation. [ABSTRACT FROM AUTHOR]

As the first line of defence, marginal zone (MZ) B cells play principal roles in clearing blood-borne pathogens during infection and are over-primed in autoimmune diseases. However, the basic mechanisms underlying MZ B-cell development are still unclear. We found here that CD19 deficiency blocked the differentiation of marginal zone precursors (MZP) to MZ B cells, whereas CD19 expression in CD19-deficient MZP rescues MZ B-cell generation. Furthermore, CD19 regulates Notch2 cleavage by up-regulating ADAM28 expression in MZP. Finally, we found that CD19 suppressed Foxo1 expression to promote ADAM28 expression in MZP. These results suggest that CD19 controls the differentiation of MZP to MZ B cells by regulating ADAM28-mediated Notch2 cleavage. Thus, we demonstrated the basic mechanisms underlying the differentiation of MZP to MZ B cells. [ABSTRACT FROM AUTHOR]

Interleukin-10-positive (IL-10+) regulatory B (Breg) cells play an important role in restraining excessive inflammatory responses by secreting IL-10. However, it is still unclear what key transcription factors determine Breg cell differentiation. Hence, we explore what transcription factor plays a key role in the expression of IL-10, a pivotal cytokine in Breg cells. We used two types of web-based prediction software to predict transcription factors binding the IL-10 promoter and found that IL-10 promoter had many binding sites for Foxd3. Chromatin immunoprecipitation PCR assay demonstrated that Foxd3 directly binds the predicted binding sites around the start codon upstream by −1400 bp. Further, we found that Foxd3 suppressed the activation of IL-10 promoter by using an IL-10 promoter report system. Finally, knocking out Foxd3 effectively promotes Breg cell production by up-regulating IL-10 expression. Conversely, up-regulated Foxd3 expression was negatively associated with IL-10+ Breg cells in lupus-prone MRL/lpr mice. Hence, our data suggest that Foxd3 suppresses the production of IL-10+ Breg cells by directly binding the IL-10 promoter. This study demonstrates the mechanism for Breg cell production and its application to the treatment of autoimmune diseases by regulating Foxd3 expression. [ABSTRACT FROM AUTHOR]

Interleukin-12 family cytokines have emerged as critical regulators of immunity with some members (IL-12, IL-23) associated with disease pathogenesis while others (IL-27, IL-35) mitigate autoimmune diseases. Each IL-12 family member is comprised of an α and a β chain, and chain-sharing is a key feature. Although four bona fide members have thus far been described, promiscuous chain-pairing between alpha (IL-23p19, IL-27p28, IL-12/IL-35p35) and beta (IL-12/IL-23p40, IL-27/IL-35Ebi3) subunits, predicts six possible heterodimeric IL-12 family cytokines. Here, we describe a new IL-12 member composed of IL-23p19 and Ebi3 heterodimer (IL-39) that is secreted by LPS-stimulated B cells and GL7+ activated B cells of lupus-like mice. We further show that IL-39 mediates inflammatory responses through activation of STAT1/STAT3 in lupus-like mice. Taken together, our results show that IL-39 might contribute to immunopathogenic mechanisms of systemic lupus erythematosus, and could be used as a possible target for its treatment. [ABSTRACT FROM AUTHOR]

Complement 5a (C5a) and Interleukin-17 (IL-17) are two important inflammatory mediators in sepsis. Here we studied the mechanisms underlying regulation of IL-17 by anaphylatoxin C5a. We found that C5a blockade increased the survival rate of mice following cecal ligation and puncture (CLP)-induced sepsis and decreased IL-17 expression in vivo. IL-17 was secreted mainly by γδ T cells in this model. Importantly, our data suggest that C5a participates in the regulation of IL-17 secretion by γδ T cells. Dendritic cells (DC) were found to act as a 'bridge' between C5a and γδ T cells in a mechanism involving IL-6 and transforming growth factor β (TGF-β). These results imply that C5a affects the crosstalk between DC and γδ T cells during sepsis development, and this may result in a large production of inflammatory mediators such as IL-17. [ABSTRACT FROM AUTHOR]

T cell immunoglobulin and mucin domain protein 3 (Tim‐3) is an immune checkpoint inhibitor in T cells and innate immune cells. The deregulated upregulation of Tim‐3 is related to immune exhaustion in tumour and viral infection. To overcome Tim‐3‐mediated immune tolerance, we developed a novel monoclonal antibody against human Tim‐3 (L3G) and investigated its roles in inhibiting Tim‐3 signalling and overcoming immune tolerance in T cells and monocytes/macrophages. The administration of L3G to cultured peripheral blood mononuclear cells (PBMCs) significantly increased the production of IFN‐γ and IL‐2 and the expression of type I interferon. The administration of L3G also increased the production of IFN‐γ, IL‐8 and type I interferon in U937 cells and primary monocytes. We investigated the mechanisms by which L3G enhances pro‐inflammatory cytokine expression, and our data show that L3G enhances STAT1 phosphorylation in both monocytes/macrophages and T cells. Finally, in an H1N1 infection model of PBMCs and U937 cells, L3G decreased the viral load and enhanced the expression of interferon. Thus, we developed a functional antibody with therapeutic potential against Tim‐3‐mediated infection tolerance. [ABSTRACT FROM AUTHOR]

We previously showed that γδT cells are involved in the pathogenesis of sepsis, but, the underlying mechanisms remained unclear. The present study demonstrates, for the first time, that γδT cells express the complement C5a receptor (C5aR, CD88) and that CD88 expression in γδT cells was up-regulated in mice following sepsis both at protein and mRNA levels. Complement C5a itself contributed to the regulation of C5aR expression on γδT cells, as (i) neutralization of C5a in vivo prevented the expression of C5aR on γδT cells in septic mice and (ii) incubation of mouse spleen cells or purified γδT cells with recombinant C5a in vitro increased CD88 expression by γδT cells at both protein and mRNA levels. C5a receptor on γδT cells also mediates increased interleukin-17 (IL-17) expression as incubation of mouse spleen cells or purified γδT cells with recombinant C5a promotes the IL-17 expression by γδT cells. Ligation of the C5aR on γδT cells activated the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, which enhances CD88 expression and promotes IL-17 secretion. These results demonstrate that C5a acts directly on the C5aR expressed on γδT cells, resulting in cell activation, and subsequently enhances their capacity for IL-17 production. The up-regulation of the PI3K/Akt pathway following C5a stimulation contributes to up-regulation of γδT-cell function. [ABSTRACT FROM AUTHOR]

The application of anti-CD3 F(ab')2 monoclonal antibodies recently has been expanded to treat established autoimmune diseases including type 1 diabetes. However, the underling mechanisms remain largely unclear. Here, we report that short-phase administration of anti-CD3 F(ab')2 antibodies efficiently converted new-onset diabetic nonobese diabetic mice into normoglycemia and re-established pancreatic β-cell specific tolerance, this therapeutic effect lasting over 40 weeks. The understanding of involving mechanism revealed the generation of a population of immunoregulatory CD1d-restricted natural killer T (NKT) cells, which was marked by enhanced Th2 response and secreting more IL-10. In vivo neutralization of IL-4 and/or IL-10 bioactivity abrogated this anti-CD3-mediated effect. Importantly, when cotransfer of remitting mice derived NKT cells into NOD-severe combined immunodeficient (NOD.scid) mice with diabetogenic cells, these NKT cells were sufficient to delay or prevent the onset of diabetes. These data suggested that CD1d-restricted NKT cells might play a critical role in anti-CD3 antibody induced diabetes remission and immune tolerance restoration. [ABSTRACT FROM AUTHOR]