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关键词： Spondyloarthritis   Cardiovascular disease   Cancer   Comparative safety   Tofacitinib   TNF inhibitors  

摘要： Objectives: To compare the risk of cardiovascular disease (CVD) and common solid cancers between JAK inhibitors (JAKi) versus TNF or IL-17 inhibitors, among people with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA). Methods: We used real-world electronic health records data from a predominantly North American population of PsA or axSpA. Initiators of JAKi (tofacitinib or upadacitinib) and TNFi were 1:1 propensity score matched. Cox models were used to compare time to CVD (acute myocardial infarction, stroke or revascularization) or common solid cancers (breast, colorectal, lung or prostate) over 3 years. Analyses were repeated for JAKi versus IL-17i. We performed sensitivity analyses with follow-up over 1 or 5 years, in those aged >= 65 years, or those initiating treatment before 2021. Results: The JAKi vs TNFi comparison included 2,200 matched individuals in each group over 3,092 and 4,618 person-years, respectively. Compared to TNFi, JAKi was not associated with higher risk of CVD (HR 0.977;95% 0.632, 1.510) or cancer (HR 0.710;0.462, 1.091) over 3 years' follow-up. JAKi vs IL-17i comparison included 2,287 individuals over 3,190 and 4,312 person-years, respectively. Compared to IL-17i, JAKi was not associated with risk of CVD (HR 1.114;0.720,1.722) or cancer (HR 0.737;0.484,1.122). Results across stratified analyses were directionally concordant. Conclusions: These results are reassuring that among a large population of people with PsA or axSpA, JAKi was not associated with increased risk of CVD or common solid cancers, compared to TNFi or IL-17i initiators. Ongoing monitoring of cardiovascular and cancer risks is needed.

摘要： [This corrects the article DOI: 10.1093/ofid/ofae327.].

关键词： HLA-B*39:01:01:31   HLA-genotyping   illumina   next generation sequencing   novel allele  

摘要： The HLA-B*39:01:01:31 allele differs from HLA-B*39:01:01:03 by a single nucleotide substitution in intron 2.

关键词： antigen-presenting cells   microglia   M & uuml   ller cells   retina   T-cells  

摘要： Glia antigen-presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. However, the intricate mechanisms underlying their local coordination and activation remain unclear. Our study integrates an animal model of retinal injury, retrospective analysis of human retinas, and in vitro experiments to gain insights into the crucial role of antigen presentation in neuroimmunology during retinal degeneration (RD), uncovering the involvement of various glial cells, notably M & uuml;ller glia and microglia. Glial cells act as sentinels, detecting antigens released during degeneration and interacting with T-cells via MHC molecules, which are essential for immune responses. Microglia function as APCs via the MHC Class II pathway, upregulating key molecules such as Csf1r and cytokines. In contrast, M & uuml;ller cells act through the MHC Class I pathway, exhibiting upregulated antigen processing genes and promoting a CD8+ T-cell response. Distinct cytokine signaling pathways, including TNF-alpha and IFN Type I, contribute to the immune balance. Human retinal specimens corroborate these findings, demonstrating glial activation and MHC expression correlating with degenerative changes. In vitro assays also confirmed differential T-cell migration responses to activated microglia and M & uuml;ller cells, highlighting their role in shaping the immune milieu within the retina. In summary, our study emphasizes the involvement of retinal glial cells in modulating the immune response after insults to the retinal parenchyma. Unraveling the intricacies of glia-mediated antigen presentation in RD is essential for developing precise therapeutic interventions for retinal pathologies.

关键词： Wutou-Guizhi decoction   Rheumatoid arthritis   Network pharmacology   IL-17 signaling pathway   Stigmasterol  

摘要： As a widely recognized traditional Chinese medicine (TCM) decoction prescription in China, numerous studies have shown that Wutou-Guizhi decoction (WTGZD) exhibits significant therapeutic efficacy for Rheumatoid arthritis (RA). Nevertheless, the underlying molecular mechanisms have yet to be fully elucidated. This study aims to establish a database of active ingredients for WTGZD and identify RA-related target genes. The WTGZD-RA-Potential target gene network and protein-protein interaction network were constructed, followed by gene ontology (GO) analysis and functional enrichment analysis utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG). Cell proliferation was confirmed through CCK8 assay. Target gene identification was performed via real-time PCR using quantitative methods, and western blot analysis was conducted. In the course of this investigation, 95 active components of drugs and 34 targets associated with rheumatoid arthritis were identified. Through the utilization of network pharmacology analysis, we were able to identify a total of 17 essential active components of WTGZD and pinpoint 12 significant targets linked to rheumatoid arthritis (RA). Our findings suggest a consistent interaction between the key components of WTGZD and the critical targets associated with RA. Subsequent qPCR analysis revealed that stigmasterol, a principal constituent of WTGZD, exhibited inhibitory effects on the expression of various RA-related factors, such as TNF-alpha, IL-1 beta, MAPK8, MMP1, MMP3, and MMP9. Moreover, WTGZD effectively mitigated the increased protein expression of MMP-1 and MAPK8 induced by LPS stimulation, both of which are integral components of the IL-17 signaling pathway. These results suggest that WTGZD may play a significant role in the therapeutic intervention of rheumatoid arthritis by suppressing inflammatory immune responses.

关键词： antigen presentation/processing   cytokines   endothelial cells   neuroimmunology  

摘要： Calcitonin gene-related peptide (CGRP) biases Langerhans cell (LC) Ag presentation to CD4+ T cells towards Th17-type immunity through actions on endothelial cells (ECs). We now report further evidence that IL-6 signalling at responding T cells mediates this effect. This CGRP effect was absent with ECs from IL-6 KO mice. Exposure of LCs, but not T cells, to IL-6 enhanced IL-6 and IL-17A production and reduced IFN-gamma in the T-cell response. Pretreatment of LCs with IL-6 receptor alpha-chain (IL-6R alpha) antibodies prior to IL-6 exposure significantly inhibited these responses. However, T-cell pretreatment with an IL-6/IL-6R alpha chimera mimicked the effect of IL-6 pretreatment of LCs on T-cell responses. When this experiment was performed in the presence of the ADAM17 and ADAM10 inhibitor TAPI-1 during LC pretreatment of LCs and during the Ag presentation culture, release of soluble IL-6R alpha chains into the medium was very significantly reduced, but this did not affect levels of T-cell cytokine release. Interestingly, LC exposure to IL-6 significantly increased LC IL-6 expression. Furthermore, pretreatment of T cells with antibodies against the IL-6 receptor beta-chain significantly inhibited the IL-6 effect. CGRP may stimulate ECs in lymphatics and/or lymph nodes to produce IL-6 which likely results in migrating LCs nonclassically presenting IL-6. Furthermore, we found that IL-6 induces IL-6 production by LCs, suggesting an autocrine amplification pathway for this effect.

关键词： COVID-19   IFN-gamma   Polymorphism   SARS-CoV-2  

摘要： The severity of coronavirus disease 2019 (COVID-19) varies significantly among individuals, which indicates the impact of individual differences on disease. Emerging evidence suggests that genetic factors play a crucial role in determining the severity of the disease. For instance, variants in the interferon-gamma (IFN-gamma) gene, such as the +874 T/A single nucleotide polymorphism (SNP), have been linked to altered immune responses and may influence the severity of COVID-19. We aim to determine the influence of the IFN-gamma +874T/A SNP on the clinical outcomes of COVID19 patients. We investigated the SNP at position +874 in the promoter region of the IFN-gamma gene in 416 individuals (206 critically ill COVID-19 patients and 210 healthy controls) in northwestern of Iran. Genomic DNA was extracted from the blood leukocytes of the patients, and the SNP was analyzed using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method. The AA genotype was significantly more frequent in critically ill COVID-19 patients than in healthy controls. Conversely, the AT and TT genotypes were more common in healthy controls. Furthermore, the A allele was more frequent in critically ill patients than in healthy controls, while the T allele was more frequent in healthy controls compared to critically ill patients. Our study identified the IFN-gamma +874T/A SNP as a significant genetic factor influencing COVID-19 severity. This finding underscores the critical role of genetic factors in disease severity and highlights the importance of personalized medicine in managing COVID-19.

关键词： HLA-C   NGS   novel allele  

摘要： Novel HLA-C*07:1165, HLA-C*07:1166, HLA-C*07:02:161 alleles and confirmatory HLA-C*07:02:156 allele were detected during the HLA typing process.

关键词： Consent   Immuno-modulation   Immunological   Ligand   Messenger ribonucleic acid (mRNA)   Molecular genetic   Pathogenesis   Polymorphism   Prevalence  

摘要： BackgroundNon-alcoholic fatty liver disease (NAFLD) in non-obese patients is pathophysiologically distinct, exhibiting common immunological link with type-2 diabetes mellitus (T2DM). This study aims to delineate the role of Toll-like receptor 2 (TLR2)-mediated immuno-modulation along with its association with fibroblast growth factor receptor 4 (FGFR4) and its ligand fibroblast growth factor 19 (FGF19) in the pathogenesis of NAFLD without or with *** samples were collected from patients with NAFLD (n = 90), NAFLD with T2DM (n = 90) and healthy cohorts (n = 90) with consent and clinical records. Real-time polymerase chain reaction (PCR), enzyme-linked immunoassay (ELIZA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to analyze messenger ribonucleic acid (mRNA), protein expression and gene *** molecular genetic analysis revealed the prevalence of variant allele(A) in FGFR4 gene in both cases compared to controls. The mRNA expression of FGF19 and TLR2 exhibited significant upregulation in NAFLD without T2DM compared to NAFLD with T2DM. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12) showed upregulation in both disease cohorts compared to control while IL-10 showed significant downregulation in NAFLD with T2DM compared to the other two cohorts. Correlation analysis between FGF19 and TLR2 revealed significant positive association in both NAFLD with and without T2DM. The Th1:Th2 ratio showed significant upregulation in NAFLD with T2DM compared to NAFLD without *** conclusion, elevated serum endotoxin levels appear to contribute to NAFLD and T2DM development. Upregulated FGF19 seems to be protective against developing T2DM in NAFLD patients. Higher TLR2, TNF-alpha and IL-12 expression in NAFLD without T2DM suggests a Th1 bias in its pathogenesis, while reduced IL-10 in NAFLD with T2DM implies a more skewed Th1 state in this condition.