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关键词： L. plantarum BX62   Rheumatoid arthritis   Oxidative stress   Methotrexate   Bone damage  

摘要： This study explored the effect of antioxidant Lactiplantibacillus plantarum BX62 (2x109CFU/ml) on RA and elucidated its underlying mechanisms using a collagen induced arthritis rat model. Results showed L. plantarum BX62 reduced oxidative stress, decreased the levels of inflammatory cytokines in the serum, and increased antiinflammatory interleukin-10 levels. Bone damage mitigation was confirmed via histology and micro-computed tomography analyses. Furthermore, L. plantarum BX62 restored immune balance and CD4+/CD8+ T cell ratio in the spleen. Downregulations of NLRP3, Cleaved Caspased-1, Cleaved IL-1R, RANKL, p-AKT, p-mTOR, and p62, and upregulations of OPG and Beclin-1 proteins were also observed in L. plantarum BX62 group. Meanwhile, The stable organ coefficients of L. plantarum BX62 demonstrated its safety for oral administration. Overall, L. plantarum BX62 demonstrated preventive effects against RA progression by reducing oxidative stress, modulating NLRP3/Caspase-1/IL-1R, AKT/mTOR pathways, balancing autophagy, and enhancing bone protection;thus, making it a formidable probiotic strain for curing RA.

摘要： Ineffective erythropoiesis (IE) commonly underlies anemia in congenital disorders. However, the causes of IE remain largely unknown. Recently, attention has been drawn to the involvement of nucleated erythrocytes in immune responses, providing a new perspective for exploring the etiology of IE. In this study, we found that the kdm4b-/- mutant zebrafish developed an IE-like defect, including impaired terminal maturation and apoptosis of erythroblasts, as confirmed by observations in Kdm4b-/- mutant mice. Thus, the Kdm4b mutant serves as an appropriate model for studying IE. Mechanistically, kdm4b primarily targets interleukin 6 (il6) to regulate the previously underrated immune activity of embryonic erythroblasts. The erythroblast-secreted Il6, in the absence of kdm4b, increased pro-inflammatory activities of myeloid cells and elevated T cell counts. Meanwhile, the activated Il6-pStat3 signaling elevated mitochondrial oxidative stress, leading to the maturation arrest of erythroblasts. Collectively, we demonstrate an important role for kdm4b in coordinating terminal maturation and immune function in erythroblasts. These findings might shed light on our understanding of the etiology of IE and the discovery of new effective compounds.

关键词： allergen immunotherapy   allergic rhinitis   B-lymphocyte cell   house dust mite   mucosal-associated invariant T cells  

摘要： BackgroundMucosal-associated invariant T cells (MAIT) are emerging as important regulators at mucosal surfaces. While these cells have been linked to a Th1-biased immune response and support for B cells, their roles in allergic diseases characterised by type 2 inflammation remain elusive. The study seeks to characterise MAIT cells in house dust mite (HDM)-induced allergic rhinitis (AR) and subsequent allergen immunotherapy (AIT), aiming to elucidate their clinical significance in AR and potential to enhance AIT *** cells were assessed in patients with AR and individuals undergoing AIT. The ratio and cytokine-producing capacity of these cells were analysed to explore their correlations with AR progression and their responsiveness to HDM extracts and MAIT cell-specific *** AR patients, there was an increase in the ratios of circulating MAIT cells and tonsil follicular T helper-like MAIT cells, alongside a decrease in the IFN-gamma-producing MAIT cells. AIT restored their IFN-gamma producing capacity, which was further boosted by T cell receptor (TCR) activation using MAIT cell-specific agonist-loaded artificial antigen-presenting cells (aAPCs). Synergistic effects of aAPCs and HDM enhance MAIT cell activation and IFN-gamma production while reducing HDM-induced IgE levels in PBMC cocultures. Moreover, higher ratios of MAIT cells and IFN-gamma-producing MAIT cells correlated with decreased IgE and increased IgG4 and improved clinical outcomes during *** findings underscore the compromised IFN-gamma-producing MAIT cells in AR and their restoration following AIT and TCR stimulation, highlighting the cell's therapeutic potential and predictive value for clinical outcomes in AR and AIT.

关键词： Nonmyeloablative   Allogeneic hematopoi-   etic cell transplantation   Sickle cell disease   Alemtuzumab   Sirolimus   Immunodepletion   Mixed myeloid chime-   rism  

摘要： Nonmyeloablative (NMA) conditioning is being used increasingly with success in matched related donor (MRD) and alternative donor allogeneic hematopoietic cell transplantation (allo-HCT) in individuals with sickle cell disease (SCD). Advantages include decrease toxicity and applicability in patients otherwise unable to tolerate conditioning regimens due to end-organ damage or age. We aimed to add to published data outcomes of two similar NMA conditioning protocols, termed Protocol 1 (*** ID NCT00061568) and Protocol 2 (*** ID: NCT02105766)) in mainly adult patients with SCD to evaluate the safety, toxicity, and success of these regimens in individuals at high-risk for poor transplantation-related outcomes. We also evaluated the tolerability and outcomes of Protocol 2, which included preconditioning immunodepletion, in patients at even higher risk of T cell-mediated rejection or plasma/B cell-mediated anti-donor erythrocyte antibody production-the latter due to ABO incompatibility or recipient RBC alloimmunization to a donor antigen. Finally, we evaluated the incidence and trajectory of mixed donor myeloid chimerism over time following allo-HCT. In this retrospective analysis of the 2 prospective phase 2 NMA transplant protocols, 91 individuals with SCD or transfusion-dependent b-thalassemia underwent MRD allo-HCT at the National Heart, Lung, and Blood Institute;regimens contained alemtuzumab, low-dose radiation, and sirolimus for graft-versus-host disease (GVHD) prophylaxis with or without preconditioning immunodepletion with pentostatin and oral cyclophosphamide (Protocol 2). In the total cohort of 91 transplantation recipients, outcomes were favorable with timely neutrophil and platelet engraftment (median, 21 days [range, 7 to 67 days] and 21 days [range, 10 to 112 days], respectively), minimal high-grade acute GVHD and their values. In analyzing each protocol separately, outcomes were comparable except for higher cytomegalovirus reac

关键词： B cell   differentiation   exosomes   IL-10   mesenchymal stem cells  

摘要： The role of IL-10-producing regulatory B cells in inflammatory diseases has recently gained substantial attention. Here, we evaluated the function of mouse bone marrow mesenchymal stem cell-derived exosomes (BMMSC-Exos) and their effect on B-cell differentiation. This study aimed to establish an association between BMMSC-Exos and purified B cells and further explored the anti-inflammatory effect of B10 cells. The expression of inflammatory factors, such as IL-1 beta, TNF-alpha, and bone metabolism-related factors, including RANKL, OPG, and secreted IL-10, was investigated by RT-qPCR and ELISA. Populations of CD1dhighCD5+ B cells were analyzed by flow cytometry and immunofluorescence. Cell viability was assessed by CCK8 assay. The results showed that when B cells were separated from BMMSCs by Transwell, IL-1 beta, TNF-alpha, and RANKL were downregulated, whereas IL-10, OPG/RANKL, and CD1dhighCD5+ Breg proportion were upregulated in the cocultured groups. Conversely, when B cells were cultured with BMMSC-Exos, increasing concentrations of exosomes increased the proportion of CD1dhighCD5+ and IL-10+CD45+ Bregs;however, the secretion of both pro-inflammatory cytokines and IL-10 were decreased. We found that BMMSC-Exos induce the differentiation of B cells toward the CD1dhighCD5+ and IL-10+CD45+ Breg phenotype but cannot increase the secretion of IL-10 in vitro.