Myasthenia gravis (MG) is a rare autoimmune disease. Although the impact of immune cell disorder in MG has been extensively studied, little is known about the transcriptomes of individual cells. Here, we assessed the transcriptional profiles of 39,243 cells by single-cell sequencing and identified 13 major cell clusters, along with 39 subgroups of cells derived from patients with new-onset myasthenia gravis and healthy controls. We found that B cells, CD4+ T cells, and monocytes exhibited more heterogeneity in MG patients. CD4+ T cells were expanded in MG patients. We reclustered B cells and CD4+ T cells, and predict their essential regulators. Further analyses demonstrated that B cells in MG exhibited higher transcriptional activity towards plasma cell differentiation, CD4+ T cell subsets were unbalanced, and inflammatory pathways of monocytes were highly activated. Notably, we discovered a disease-relevant subgroup, CD180− B cells. Increased CD180− B cells in MG are indicative of a high IgG composition and were associated with disease activity and the anti-AChR antibody. Together, our data further the understanding of the cellular heterogeneity involved in the pathogenesis of MG and provide large cell-type-specific markers for subsequent research.
The innovation value chain is an effective tool for analysing innovation activities and reflects the process of value creation and increase in innovation activities. From the perspective of innovation value chains, we divided patent innovation activities into three stages: knowledge innovation stage, applied research stage and patent commercialization stage. The panel data from 64 universities directly managed by the Ministry of Education from 2009 to 2017 were used and several conclusions were drawn: 1) In the initial stage of knowledge innovation, the fundamental research fund plays a crucial promoting role, and knowledge innovation achievements are mainly published academic papers. 2) In the applied research stage, the knowledge innovation in the early stage and the fund investment in R&D activities have a significant positive effect on the patent output of universities, but the personnel investment has a negative effect. 3) In the final stage of patent commercialization, preliminary research results have a positive impact on patent commercialization, whose marginal effect depends on the industry-university-research relationship, external competition and reputation of the university. The evidence showed that there is a feedback channel between university patent commercialization and knowledge innovation, and new knowledge generated by the interaction with the outside world in the process of patent commercialization was transmitted to the subject of knowledge innovation through this channel, forming a virtuous dynamic cycle. By analysing the driving factors of the value chain of patent innovation in colleges and universities, we provided empirical evidence for the operation mechanism and policy formulation of college patents in China. PLOS ONEPLOS ONE | https://doi.org/10.1371/journal.pone.
Background: We investigated the correlation between glucose metabolism patterns of different immune cells and the metabolic regulatory signaling pathways in myasthenia gravis (MG) and aimed to identify therapeutic targets for MG.Methods: We isolated peripheral blood mononuclear cells (PBMCs) and sorted CD19 + B cells, dendritic cells (DCs), CD4 + T cells, CD8 + T cells, CD4 + CD25 + regulatory T cells (Tregs), CD4 + CD25 − T cells, and T helper (Th) cells such as Th1, Th2, and Th17 cells. Then, we detected the expression levels of PI3K/AKT/ mTOR-HIF-1α, GLUT1, hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) by RT-PCR, measured the oxygen consumption rate and extracellular acidification rate of ex vivo freshly sorted cells using the Seahorse XF e 96 Analyzer. In addition, we compared the glycolysis levels using these cells from the same MG patients. By performing in vitro experiments, we measured, the mRNA expression levels of mTOR, HIF-1α, B cell activating factor receptor (BAFF-R), GLUT1, HK, PFK, and PK, in addition to ECAR profiles, frequency of CD80 and CD86, and IgG levels from the culture supernatant of B cells (isolated from MG patients) treated with rapamycin and PX-478 (selective mTOR and HIF-1α inhibitor, respectively) from.Results: Except PBMCs, Th2 and CD8 + T cells, the expression levels of the key enzymes involved in glycolysis and HIF-1α were significantly higher in B cells, DCs, Tregs, CD4 + CD25 − T cells, and Th1 and Th17 cells in MG patients, and the measurement of ECAR and OCR confirmed the metabolic status. In MG patients, B cells and DCs showed significantly higher levels of glycolysis and glycolytic capacity than CD8 + T cells, CD4 + T cells and its subsets. In vitro, except IgG levels, the increased glycolysis levels, expression of key glycolytic enzymes, BAFF-R and frequency of CD80 and CD86 of B cells, could be inhibited by rapamycin and PX-478.Conclusions: Different subtypes of immune cells in MG exhibit different glucose metabolism patterns.The mTOR-HIF-1α signaling pathway might be the immunometabolism reprogramming checkpoint of glycolysis-dependent activated B cells in MG.
Background: Tacrolimus has been recommended as an effective immunosuppressant for patients with myasthenia gravis (MG), while the high price, variable bioavailability, and narrow therapeutic window restrict its clinical application. Wuzhi capsule (WZC) could improve tacrolimus blood concentration by inhibiting the metabolism of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). There are few studies focused on the coadministration of WZC and tacrolimus in autoimmune diseases. This study was aimed at quantifying the efficacy and safety of coadministration of WZC and tacrolimus in adult Chinese patients with MG. Methods: In this retrospective study, 122 patients with MG on tacrolimus were enrolled. The initial tacrolimus dose was 2 mg/d. Patients with standard initial tacrolimus concentration were classified into group A (standard-dose group). Those failed to reach target concentration were divided into group B (high-dose group) and group C (co-administering WZC group), according to treatment adjustment of increasing tacrolimus dose and coadministration of WZC, respectively. A logistic analysis was used to identify factors associated with clinical outcome. Adverse drug reactions (ADRs) were recorded for safety analysis. Results: The tacrolimus concentration after coadministration of WZC was remarkably increased. It was higher compared with simply increasing the tacrolimus dose (p<0.001). The multivariate logistic analysis indicated that the baseline quantitative MG score was a predictive factor for clinical outcomes (OR=0.189; 95% CI 0.082-0.436; p<0.001). Fourteen patients (11.5%) reported ADRs after tacrolimus therapy. ADRs incidence was not related to WZC coadministration. Conclusion:The coadministration of WZC and tacrolimus can substantially elevate the tacrolimus concentration. It is a safe and economic treatment for adult Chinese patients with MG. Patients with a worse disease condition tend to present a better clinical outcome after tacrolimus therapy.
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