Cancer immunotherapy by immune checkpoint blockade has been effective in the treatment of certain tumors. However, the association between immune checkpoints and autoimmune diseases remains elusive and requires urgent investigation. Primary immune thrombocytopenia (ITP), characterized by reduced platelet count and a consequent increased risk of bleeding, is an autoimmune disorder with a hyper-activated T cell response. Here, we investigated the contribution of immune checkpoint-related single-nucleotide polymorphisms (SNPs), including CD28, ICOS, PD1, TNFSF4, DNAM1, TIM3, CTLA4, and LAG3 to the susceptibility and therapeutic effects of ITP. In this case-control study, 307 ITP patients and 295 age-matched healthy participants were recruited. We used the MassARRAY system for genotyping immune checkpoint-related SNPs. Our results revealed that rs1980422 in CD28 was associated with an increased risk of ITP after false discovery rate correction (codominant, CT vs. TT, OR = 1.788, 95% CI = 1.178–2.713, p = 0.006). In addition, CD28 expression at both the mRNA and protein levels was significantly higher in patients with CT than in those with the TT genotype (p = 0.028 and p = 0.001, respectively). Furthermore, the T allele of PD1 rs36084323 was a risk factor for ITP severity and the T allele of DNAM1 rs763361 for corticosteroid-resistance. In contrast, the T allele of LAG3 rs870849 was a protective factor for ITP severity, and the T allele of ICOS rs6726035 was protective against corticosteroid-resistance. The TT/CT genotypes of PD1 rs36084323 also showed an 8.889-fold increase in the risk of developing refractory ITP. This study indicates that immune checkpoint-related SNPs, especially CD28 rs1980422, may be genetic factors associated with the development and treatment of ITP patients. Our results shed new light on prognosis prediction, disease severity, and discovering new therapeutic targets.

Altered microenvironmental stiffness is a hallmark of inflammation. It is sensed by the mechanically activated cation channel Piezo1 in macrophages to induce subsequent immune responses. However, the mechanism by which the mechanosensitive signals shape the metabolic status of macrophages and tune immune responses remains unclear. We revealed that Piezo1-deficient macrophages exhibit reduced aerobic glycolysis in resting or liposaccharide (LPS)-stimulated macrophages with impaired LPS-induced secretion of inflammatory cytokines in vitro. Additionally, pretreatment with the Piezo1 agonist, Yoda1, or cyclical hydrostatic pressure (CHP) upregulated glycolytic activity and enhanced LPS-induced secretion of inflammatory cytokines. Piezo1-deficient mice were less susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Yoda1 treatment aggravated colitis. Mechanistically, we found that Piezo1 activation promotes aerobic glycolysis through the Ca2+-induced CaMKII-HIF1α axis. Therefore, our study revealed that Piezo1-mediated mechanosensitive signals Piezo1 can enhance aerobic glycolysis and promote the LPS-induced immune response in macrophages.

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Immune thrombocytopenia (ITP) is an autoimmune disorder, in which megakaryocyte dysfunction caused by an autoimmune reaction can lead to thrombocytopenia, although the underlying mechanisms remain unclear. Here, we performed single-cell transcriptome profiling of bone marrow CD34+ hematopoietic stem and progenitor cells (HSPCs) to determine defects in megakaryopoiesis in ITP. Gene expression, cell-cell interactions, and transcriptional regulatory networks varied in HSPCs of ITP, particularly in immune cell progenitors. Differentially expressed gene (DEG) analysis indicated that there was an impaired megakaryopoiesis of ITP. Flow cytometry confirmed that the number of CD9+ and HES1+ cells from Lin−CD34+CD45RA− HSPCs decreased in ITP. Liquid culture assays demonstrated that CD9+Lin−CD34+CD45RA− HSPCs tended to differentiate into megakaryocytes; however, this tendency was not observed in ITP patients and more erythrocytes were produced. The percentage of megakaryocytes differentiated from CD9+Lin−CD34+CD45RA− HSPCs was 3-fold higher than that of the CD9− counterparts from healthy controls (HCs), whereas, in ITP patients, the percentage decreased to only 1/4th of that in the HCs and was comparable to that from the CD9− HSPCs. Additionally, when co-cultured with pre-B cells from ITP patients, the differentiation of CD9+Lin−CD34+CD45RA− HSPCs toward the megakaryopoietic lineage was impaired. Further analysis revealed that megakaryocytic progenitors (MkP) can be divided into seven subclusters with different gene expression patterns and functions. The ITP-associated DEGs were MkP subtype-specific, with most DEGs concentrated in the subcluster possessing dual functions of immunomodulation and platelet generation. This study comprehensively dissects defective hematopoiesis and provides novel insights regarding the pathogenesis of ITP.

Introduction Hereditary human coagulation factor VII (FVII) deficiency is an inherited autosomal recessive hemorrhagic disease involving mutations in the F7 gene. The sites and types of F7 mutations may influence the coagulation activities of plasma FVII (FVII: C) and severity of hemorrhage symptoms. However, the specific mutations that impact FVII activity are not completely known. Methods We tested the coagulation functions and plasma activities of FVII in seven patients recruited from six families with hereditary FVII deficiency and sequenced the F7 gene of the patients and their families. Then, we analyzed the genetic information from the six families and predicted the structures of the mutated proteins. Results In this study, we detected 11 F7 mutations, including four novel mutations, in which the mutations p.Phe84Ser and p.Gly156Cys encoded the Gla and EGF domains of FVII, respectively, while the mutation p.Ser339Leu encoded the recognition site of the enzymatic protein and maintained the conformation of the catalytic domain structure. Meanwhile, the mutation in the 5′ untranslated region (UTR) was closely associated with the mRNA regulatory sequence. Conclusion We have identified novel genetic mutations and performed pedigree analysis that shed light on the pathogenesis of hereditary human coagulation FVII deficiency and may contribute to the development of treatments for this disease.

Summary Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the imbalance of CD4+ T cell subsets play a key role in the pathogenesis. Since T cells highly depend on metabolism for their function, we hypothesized that T cell dysfunction may be due to intracellular metabolic reprogramming. We found that in ITP, T cell metabolism shifts from oxidative phosphorylation to glycolysis. Empagliflozin, a sodium–glucose cotransporter 2 inhibitor, has shown regulatory metabolic effects on proximal tubular epithelial cells and cardiac cells beyond glucose lowering. However, the effects of empagliflozin on T cells remain unknown. To further investigate the metabolic dysfunction of CD4+ T cells in ITP, we explored the effect of empagliflozin on CD4+ T‐cell differentiation in ITP. Our results are the first to show that increased glycolysis in CD4+ T cells resulted in an unbalanced CD4+ T‐cell population. Furthermore, empagliflozin can affect the differentiation of CD4+ T‐cell subsets by inhibiting Th1 and Th17 cell populations while increasing Tregs. Empagliflozin appears to regulate CD4+ T cells through inhibiting the mTOR signal pathway. Considering these results, we propose that empagliflozin could be used as a potential therapeutic option for ITP by modulating metabolic reprogramming in CD4+ T cells.

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