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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.

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.

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

关键词： depression   high-salt diet   IL-17A  

摘要： Major depression disorder is a common illness that severely limits psychosocial functioning, affects outcomes of other diseases, and diminishes the quality of life. High-salt diet (HSD) has long been closely associated with the occurrence and development of depression, but whether or how HSD causes depression remains unclear. In this study, HSD induces depression-like behavior in mice accompanied by an increase in IL-17A production. ROR gamma t deficiency abolishes HSD-induced depression-like behavior in mice. Furthermore, gamma delta T17 cells are identified as an important cellular source of IL-17A in mice with HSD-induced depression. Depletion of gamma delta T cells using anti-TCR gamma delta antibody markedly alleviates depression-like behavior in mice with HSD. Our findings demonstrate that increased dietary salt intake facilitates the development of depression at least partially through the induction of gamma delta T17 cells. The Editors have selected this article as a highlight of the issue.

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： climate change   evolutionary processes   genetic diversity   host-parasite interactions   MHC  

摘要： Most natural populations are genetically diverse. Understanding how diversity is maintained and distributed across time and space can provide insights into the potential for evolution and extinction of populations. Immunogenetic diversity aids individuals and populations in resisting infectious disease, with many studies linking resistance to genes encoding adaptive immune responses, such as the major histocompatibility complex (MHC) genes. The MHC is particularly important for advancing our understanding of local adaptive processes and host-parasite interactions. Here, we review the emerging work and theory exploring the geographic and temporal patterns of MHC diversity in the wild and how they are shaped by selective and demographic processes. We discuss patterns of variation along latitudinal and altitudinal gradients and place this in the context of Latitude Diversity Gradient and Central Marginal Theories. We emphasize how MHC diversity is often lower at the edges of species distributions, particularly in high-latitude and high-altitude regions. We also discuss MHC diversity in natural populations facing climate change. As climate change accelerates and emerging parasites spread, reduced immunogenetic diversity could severely threaten wildlife populations, compromising their resilience and long-term survival. We propose that including immunogenetic diversity into a larger database of environmental and parasite data would allow biologists to test hypotheses regarding host-parasite coevolution and develop effective measures for conservation.