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关键词： rheumatoid arthritis   biologics   IL-6 inhibitors   infection  

摘要： Objective Investigating factors associated with drug initiation and discontinuation in patients treated with anti-IL-6 biologic DMARDs (bDMARDs) (tocilizumab or sarilumab) vs non-anti-IL-6 (anti-TNF, B or T cell therapies) bDMARDs for RA. Methods A retrospective cohort study of patients with the diagnosis of RA in the Secure Anonymised Information Linkage Databank, comprising primary and secondary care and specialist rheumatology clinic records for >90% of the population in Wales, UK. Patients initiated on first bDMARD treatment, discontinuation and clinical outcomes including infection and hospitalisation were analysed using Cox regression analysis. Results Of patients identified with RA in their primary care records, 95.7% (4691/4922) received conventional synthetic DMARDs (csDMARDs). More than one-third (36.2%) were treated with bDMARDs (1784/4922). Of these biologic-na & iuml;ve patients, 6.5% (116) were treated with anti-IL-6 bDMARDs;this treatment was associated with a previous history of infection [difference 8.8% (95% CI 1.1, 17.8)] and kidney disease [14.3% (95% CI 8.0, 22.5)]. Treatment discontinuation was significantly higher in the non-anti-IL-6 bDMARD-treated patients (23.1%) compared with the anti-IL-6 bDMARD-treated individuals (18.1%) [difference 9.4% (95% CI 1.1, 15.7)]. For those discontinuing a first line of treatment, 385 patients (23%) and 21 patients (18%) switched to an alternative bDMARD from the non-anti-IL-6 and anti-IL-6 groups, respectively. Conclusion Comorbidities, history of infection and kidney disease were associated with choosing anti-IL-6 bDMARDs in biologic-na & iuml;ve RA patients in Wales. Anti-IL-6 bDMARD-treated biologic-na & iuml;ve patients were more likely to continue treatment than non-IL-6 bDMARD-treated patients. Lay Summary What does this mean for patients? Rheumatoid arthritis (RA) can be treated by drugs called biologics. There are many biologics available that a rheumatologist can choose from based on the individual,

摘要： Epicardial adipose tissue (EAT) is a rich source of EAT-derived stromal cells (EATDS) which possess regenerative potential. CRSP2, HSP27, IL8, HSP90 and Cofilin 1 were detected in the secretome of left ventricular stromal cells under ischemia challenge. However, the association of these genes in the EAT and EATDS remain understudied. We aim to assess the status of cofilin 1, CRSP2, HSP27, IL8 and HSP90 in the EAT of myocardial infarction (MI) and Coronary Artery Bypass Graft (CABG) swine models and in vitro stimulated ischemic EATDS. Expression status of these proteins in EAT were assessed by immunostaining and in EATDS using qRT-PCR, immunostaining, and Western blot. EATDS phenotyping was performed using sc-RNAseq analysis. Cofilin 1 was increased while the other four genes were decreased in the CABG. IL8 and HSP90 were increased while CRSP2, HSP27 and cofilin 1 were decreased in the MI group. Similar trend was displayed in the expression of these genes in EATDS. Additionally, EATDS displayed versatile phenotypes at single cell resolution based on the differential expression of various gene signatures. The findings revealed novel insights into EAT/EATDS biology and further understanding regarding the EATDS sub-phenotypes would open novel avenues in translational cardiology.

关键词： 舒肺化痰汤   慢性咳嗽   嗜酸细胞活化趋化因子   免疫功能   疗效  

摘要： 目的观察舒肺化痰汤治疗儿童慢性咳嗽的临床疗效及对嗜酸细胞活化趋化因子（Eotaxin）和免疫功能的影响。方法选取2023年10月至2024年2月至广州中医药大学东莞医院（东莞市中医院）儿科就诊的60例以慢性咳嗽为主诉、符合中医证型痰湿蕴肺的病例为研究对象，根据就诊先后顺序随机分为两组。常规组给予抗生素、止咳化痰药、抗过敏药等常规西药治疗，经验方组在医药基础上给予本院自拟经验方“舒肺化痰汤”治疗，两组均连续用药14d。统计两组总有效率和不良事件发生率，比较两组T淋巴细胞亚群、Eotaxin、分泌型免疫球蛋白-A（sIgA）、嗜酸性粒细胞（EOS）、白细胞介素-4（IL-4）、白细胞介素-5（IL-5）及中医症候积分的差异。结果 经验方组总有效率高于常规组，有统计学差异（P<0.05）。经验方组和常规组治疗前中医症候积分比较，无统计学差异（P＞0.05）。经验方组和常规组治疗后咳嗽、咯痰、肺部体征等等3项主要症状评分与神乏困倦、多汗、食少纳呆、大便异常、舌质舌苔等5项次要症状评分均较治疗前降低，经验方组较常规组更低（P<0.05）。经验方组和常规组治疗前T淋巴细胞亚群、Eotaxin、sIgA、EOS、IL-4、IL-5比较，无统计学差异（P＞0.05）。经验方组和常规组治疗后CD4+、CD4+/CD8+及sIgA均较治疗前升高，经验方组较常规组更高（P<0.05）。经验方组和常规组治疗后CD8+及Eotaxin、EOS、IL-4、IL-5较治疗前降低，经验方组较常规组更低（P<0.05）。经验方组和常规组消化道反应、头晕、呼吸困难、过敏反应等总不良事件发生率比较，无统计学差异（P＞0.05）。结论舒肺化痰汤治疗儿童慢性咳嗽的可抑制Eotaxin、sIgA等因子表达，改善免疫功能，提高疗效。

关键词： Adaptive immunity   Immunology   Imprinting   Infectious disease  

摘要： The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice. Sa-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of the gene encoding sialyltransferase ST3gal4 and increases its expression by B cells, leading to hyper-α2,3sialylation of antibodies and loss of protective activity. IL-10 enhances α2,3sialylation on cell-wall-associated IsdB, IsdA, and MntC antibodies along with suppression of the respective Sa vaccines. Consistent with mouse findings, human anti-Sa antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects (high IL-10) are hypersialylated, compared with anti-Streptococcus pyogenes and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10, leading to loss of staphylococcal vaccine efficacy.

关键词： HLA-DM   HLA-DM susceptibility   MHC class-II   antigen presentation   immunopeptidome prediction   mathematical model  

摘要： Major histocompatibility complex class II (MHC-II) presents antigens to T helper cells. The spectrum of presented peptides is regulated by the exchange catalyst human leukocyte antigen DM (HLA-DM), which dissociates peptide-MHC-II complexes in the endosome. How susceptible a peptide is to HLA-DM is mechanistically not understood. Here, we present a data-driven mathematical model for the conformational landscape of MHC-II that explains the wide range of measured HLA-DM susceptibilities and predicts why some peptides are largely HLA-DM-resistant. We find that the conformational plasticity of MHC-II mediates both allosteric competition and cooperation between peptide and HLA-DM. Competition causes HLA-DM susceptibility to be proportional to the intrinsic peptide off-rate. Remarkably, diverse MHC-II allotypes with conserved HLA-DM interactions show a universal linear susceptibility function. However, HLA-DM-resistant peptides deviate from this susceptibility function; we predict resistance to be caused by fast peptide association with MHC-II. Thus, our study provides quantitative insight into peptide and MHC-II allotype parameters that shape class-II antigen presentation.

关键词： 益精利浊法   慢性非细菌性前列腺炎   TNF-α   IL-8   NIH-CPSI评分  

摘要： 目的：观察益精利浊法治疗慢性非细菌性前列腺炎（CNP）临床效果及对前列腺液肿瘤坏死因子（TNF-ɑ）、白细胞介素8（IL-8）、IL-1β等的影响。方法：选取2023年1月至2023年12月于我院进行治疗的CNP患者130例，随机分成对照组与治疗组，对照组采用常规西医治疗，治疗组在对照组的基础上增加益精利浊法治疗，观察比较两组患者疗效、前列腺液中炎症因子水平、美国国立卫生研究院慢性前列腺炎积分指数（NIH-CPSI）评分以及不良反应发生情况。结果：治疗组总有效率显著远高于对照组（P<0.05）。治疗后两组NIH-CPSI评分均有显著下降，治疗组更低（P<0.05）。治疗后两组IL-8、IL-1β、TNF-ɑ水平较治疗前有所下降，且治疗组更低（P<0.05）。治疗组与对照组不良反应总发生率分别为12.31%与10.77%，无统计学差异（P>0.05）。结论：益精利浊法治疗CNP患者疗效较好，能明显改善NIH-CPSI评分，调节炎症因子水平，且安全性较高。

摘要： OBJECTIVE:In rheumatoid arthritis (RA) and spondyloarthritis (SpA), managing persistent pain remains challenging. Little is known regarding impaired pain pathways in these patients and the impact of bDMARDs. The objective of the RAPID (Rheumatism Pain Inhibitory Descending pathways) study was to assess pain thresholds and descending pain modulation in patients with active RA or SpA following introduction of a TNF inhibitor. (TNFi) METHODS: Patients with active disease (50RA and 50SpA), naïve to bDMARD/tsDMARD and starting a TNFi were included. Patients were followed for 6 months after TNFi initiation with clinical, psychological, and pain assessment. At all visits, participants underwent quantitative sensory testing with heat and cold pain thresholds (HPT-CPT) and descending inhibition by conditioned pain modulation (CPM). Descending pain control (CPM effect) was assessed as the change in HPT (°C) following a conditioning stimulus. RESULTS:Of the 100 patients (59 women, mean age 45.8 ±14.6years), 74 completed the 6-month follow-up. Thermal pain thresholds did not significantly change during follow-up. CPM effect improved significantly during follow-up: 0.25 ±2.57°C (baseline) and 2.96 ±2.50°C at 6months (p<0.001). At the end of follow-up, mean CPM effect was significantly higher in patients without significant pain compared with patients with persistent pain >3/10 (3.25°C ±2.68 vs 2.47°C ±2.11; p=0.04) and in patients achieving remission/low disease activity compared with patients with active rheumatism (3.31°C ±2.68 vs 2.18°C ±1.87; p=0.01). CONCLUSION:In active inflammatory rheumatisms, impaired descending pain modulation, but not thermal pain thresholds, is improved after TNFi treatment, suggesting a possible effect of TNFi on central pain modulation.

关键词： Mitogens   Macaque   Monkeys   Tuberculosis   Blood   Mycobacterium tuberculosis   Blood plasma   Immune cells  

摘要： Tuberculosis (TB) is the first infectious disease to be screened-out from specified pathogen-free cynomolgus macaques (Macaca fascicularis;Mf) using in human pharmaceutical testing. Being in either latent or active stage after exposure to the Mycobacterium tuberculosis complex (MTBC), the monkey gamma-interferon release assay (mIGRA) was previously introduced for early TB detection. However, a notable incidence of indeterminate results was observed. In this study, we compared two positive mitogen references, phytohemagglutinin (PHA) that is used in the QuantiFERON-TB Gold Plus kit (QFT-PHA) and a combination of Concanavalin A and Pokeweed mitogen (ConA+PWM), in a cohort of 316 MTBC-exposed Mf. Following a 29-month follow-up of 100 selected animals, we established a new mIGRA interpretation algorithm that demonstrated a significant shift in the negative and indeterminate cases regardless of whether the QFT-PHA or ConA+PWM was used as a mitogen. That is, if the ODNIL value was <= 0.18, ODMIT-NIL > ODNIL, and the ODTB1/2-NIL were >= 0.05 and >= 25% of individual ODNIL, the mIGRA result was interpreted as 'positive'. If the ODNIL value was <= 0.18, ODMIT-NIL > ODNIL, and the ODTB-NIL was <0.05, the mIGRA result was interpreted as 'negative'. If the ODNIL value was >0.18 or the OD of mitogen references [OD(QFT-PHA) and OD(ConA+PWM)] were <= 0.18, the mIGRA result was interpreted as 'indeterminate'. As a result, negative cases increased by 10-50%, indeterminate cases decreased by 40-80%, and the number of TB-positive cases remained unchanged. Our findings highlight the critical role of mitogens as positive controls in mIGRA interpretation. This study provides the mIGRA value for the TB screening of cynomolgus macaques that enables the identification of true positive and suspicious TB cases for quarantine programs.

关键词： Extracellular vesicles   MHC cross-decoration   P2X7 receptors   transplantation  

摘要： After skin allotransplantation, intercellular transfer of donor MHC molecules mediated primarily by extracellular vesicles (EVs) released by the allograft is known to contribute to semi-direct and indirect activation of alloreactive T cells involved in graft rejection. At the same time, there is ample evidence showing that initiation of adaptive alloimmunity depends on early innate inflammation caused by tissue injury and subsequent activation of myeloid cells (macrophages and dendritic cells) recognizing danger associated molecular patterns (DAMPs). Among these DAMPs, extracellular ATP plays a key role in innate inflammation through binding to P2X7 receptors. Indeed, this process leads to the activation of the NLRP3 inflammasome and subsequent production and release of inflammatory cytokines and EVs. This prompted us to evaluate the influence of innate inflammation triggered by ATP-mediated signaling of P2X7 receptors on EV release by donor cells after skin transplantation in mice. In this article, we show that inhibition of P2X7R signaling suppresses both EV release and MHC cross-decoration of leukocytes and prolongs skin allograft survival in mice. This study reveals a novel aspect of the role of innate immunity in allotransplantation.