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关键词： Lupus   Genetic   Juvenile-onset   SLE   HLA   Haplotype   Disease activity   Complement   C4  

摘要： Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte antigen (HLA) cluster on chromosome 6p21.3 is among the most variable genomic regions, representing a major risk-factor for SLE in adults. Its impact on juvenile-onset (j)SLE remains largely unstudied. Methods: High-resolution sequencing of HLA class I (A, B, C), class II (DRB1, DQA1, DQB1) and class III (complement C2) was undertaken in the multi-ancestral UK JSLE Cohort including participants of Caucasian (n = 151, 48.8 %), Asian (n = 108, 35.0 %) and African/Caribbean (n = 50, 16.2 %) descent. Considering ancestral variation, clinical associations were tested at the level of alleles (2-field resolution), associated HLA protein sequences (antigen binding domains, 4-field resolution), and extended haplotypes (DRh). Results: Although important ancestral recombination was reported for HLA-DR2 and-DR3 haplotypes, risk associated with jSLE was conserved at related alleles (DR2h: DRB1*15:01, DQA*01:02, DQB1*06:02;DR3h: C*07:02 [Asian], B*08:01, C2 rs9332730 [Asian], DRB1*03:01). HLA-DR7 haplotypes (DRB1*07:01, OR = 0.44, 95 % CI:0.27-0.72, p = 0.0004;DQA1*02:01, OR = 0.34, 95 % CI:0.21-0.56, p = 1.8 x 10(-6)) protect Asians from jSLE development. Among 23 clinical variables recorded, the main association was found between low levels of complement C4 in Caucasian carriers of HLA-DR3h. This was not the case in Asians due to recombination with HLA-C*07:02 and integration of the C2 rs9332730 minor allele. Low C4 serum levels associated with HLA-DQA1*01:02 (DR2h) in Caucasians after excluding HLA-DR3h carriers from the analysis. An association between low white blood cell counts and HLA-A*03:01P was observed across ancestries. Conclusion: Genetic variation in the HLA cluster asso

摘要： Objectives: Transmembrane serine protease 2 (TMPRSS2) plays a key role in the entry of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and influenza A into host cells, and its elevated expression is a risk factor for the spread of viral infection. However, TMPRSS2 expression and the factors related to its induction in oral keratinocytes and fibroblasts remain largely unknown. Here, we examined TMPRSS2 expression and factors related to its induction in oral mucosal cells. Methods: TMPRSS2 expression was examined in oral keratinocytes (RT7) and fibroblasts (GT1). Subsequently, TMPRSS2 induction in was analyzed in both cell types following transfection of nucleic acid and inflammatory cytokines, such as interleukin (IL)-1 beta. Finally, the effects of IL-1 beta on STAT1 activation related to double- stranded RNA (dsRNA)-induced TMPRSS2 expression were examined. Results: RT7 and GT1 cells exhibited constitutive TMPRSS2 mRNA and protein expression. Transfection with Poly(I:C) (as a dsRNA) and poly (dA:dT) (as a double- stranded DNA [dsDNA]) increased TMPRSS2 expression. TMPRSS2 expression was also increased by IL-1 beta, but not IFN-gamma or TNF-alpha, while the combination of IL-1 beta and transfected Poly(I:C) caused a dramatic increase in TMPRSS2 expression as compared to each alone in both cell types. IL-1 beta also enhanced transfected Poly(I:C)activated STAT1 related to TMPRSS2 expression. Conclusions: TMPRSS2-expressing oral keratinocytes and fibroblasts are targets of SARS-CoV-2 and influenza A virus. TMPRSS2 expression, in cooperation with IL-1 beta, plays an important role in promoting infection during virus invasion in oral mucosal cells.

关键词： Clinical phenotypes   Juvenile dermatomyositis   Myositis-specific autoantibodies   Targeted therapies   Type 1 IFNs  

摘要： Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is associated with significant morbidity despite therapeutic advances. Distinct clinical phenotypes have emerged, which can correlate with myositis-specific antibodies. Because translational data solidify the role of type I IFNs in JDM disease pathogenesis, integration of clinical and molecular phenotyping may impact the choice of targeted therapy. This paper reviews clinical and molecular phenotyping in JDM and translational insights into immune pathogenesis that have created emerging options for targeted therapy. Targeted therapies, Type 1 IFNs

关键词： adolescents   mental health   mental illness   validation   well-being  

摘要： AimThe Mental Health Continuum-Short Form (MHC-SF) is an assessment tool used worldwide to assess emotional, social, and psychological well-being. This study examined the structure, reliability, and validity of the Japanese version of the MHC-SF among adolescents. MethodsIn total, 1588 adolescents aged 15-18 years completed the assessment (54.8% female;age mean +/- standard deviation = 16.3 +/- 0.94 years). The factor structure of the MHC-SF was evaluated using confirmatory factor analyses. The internal consistency, concurrent validity, and measurement invariance across sex and age were examined. ResultsA three-factor model of the MHC-SF yielded the best fit compared with the one- and two-factor models. Internal consistency was confirmed by a Cronbach's alpha (>0.8). Measurement invariance was observed across sex and age. Convergent and divergent validity were demonstrated by assessing the relationships with other measurements. ConclusionThis study established a three-factor model of the MHC-SF in Japanese adolescents. We confirmed the reliability and validity of the Japanese version of the MHC-SF for assessing emotional, social, and psychological well-being in adolescents.

关键词： TOP1   Microglial activation   YY1   Sleep deprivation   Neopterin   Hippocampus  

摘要： Introduction: Sleep deprivation (SD) is a common disorder in modern society. Hippocampus is an important region of the brain for learning, memory, and emotions. Dysfunction of hippocampus can lead to severe learning and memory disorder, significantly affecting quality of life. SD is accompanied by hippocampal microglia activation and a surge in inflammatory factors, but the precise mechanism remains unclear. Moreover, the ongoing unknown persists regarding how activated microglia in SD lead to neuronal damage. Topoisomerase 1 (TOP1) plays an essential role in the inflammatory process, including the tumor system and viral infection. In this study, we observed a significant elevation in TOP1 levels in the hippocampus of mice subjected to SD. Therefore, we hypothesize that TOP1 may be implicated in SD-induced microglia activation and neuronal damage. Objectives: To investigate the role of TOP1 in SD-induced microglial activation, neuronal damage, and neurobehavioral impairments, and the molecular basis of SD-induced elevated TOP1 levels. Methods: TOP1-specific knockout mice in microglia were used to study the effects of TOP1 on microglial activation and neuronal damage. Transcription factor prediction, RNA interference, ChIP-qPCR, ChIP-seq database analysis, and luciferase reporter assays were performed to explore the molecular mechanisms of YY1 transcriptional activation. Untargeted metabolic profiling was employed to investigate the material basis of YY1 transcriptional activation. Results: Knockdown of TOP1 in hippocampal microglia ameliorates SD-induced microglial activation, inflammatory response, and neuronal damage. Mechanistically, TOP1 mediates the release of IL-6 from microglia, which consequently leads to neuronal dysfunction. Moreover, elevated TOP1 due to SD were associated with neopterin, which was attributed to its promotion of elevated levels of H3K27ac in the TOP1 promoter region by disrupting the binding of YY1 and HDAC1. Conclusion: The present study

关键词： TNF   PTPRT   Goat   InDel   Brucella  

摘要： Brucella, an intracellular facultative coccidia, causes brucellosis, which poses a significant threat to livestock farming and public health, and screening for candidate genes associated with resistance to brucellosis is considered an effective strategy for controlling the transmission and infection of this disease. In this context, we detected InDel genetic variants of the tumor necrosis factor (TNF) and protein tyrosine phosphatase receptor T (PTPRT) genes in the Shaanbei White Cashmere (SWBC) goat and analyzed the correlation between their polymorphisms and the risk of brucellosis infection in goats. The results indicated that the TNF rs669191919 and PTPRT rs639317914 loci were polymorphic in the examined goat populations. Both loci exhibited a 13 bp InDel deletion and resulted in three genotypes: insertion/insertion (II), insertion/deletion (ID), and deletion/deletion (DD), with II genotypes and I alleles occurring at higher frequencies. The polymorphism information content (PIC) values suggested that both InDel variant loci were moderately polymorphic (0.25 < PIC <0.50). Furthermore, association analysis revealed that none of the four established genetic models codominant, dominant, recessive, and allele showed an association between the polymorphisms at the rs669191919 and rs639317914 loci and the risk of brucellosis in goats (P > 0.05). Bioinformatics analyses indicated that the rs669191919 and rs639317914 loci specifically bind to the transcription factors upstream transcription factor 1 (USF1) and nescient helix-loop-helix 1 (NHLH1), respectively. In summary, our findings suggest that polymorphisms at the TNF rs669191919 and PTPRT rs639317914 loci do not influence resistance to brucellosis in goats. However, investigations into the specific binding of these polymorphic loci to transcription factors may represent a novel avenue for exploring the mechanisms underlying resistance to brucellosis in livestock.

关键词： Follicular T cells   Low-dose IL-2   Rheumatoid arthritis  

摘要： ObjectiveThis study is aimed at investigating the characteristics of RA patients at different stages and at evaluating the potential application of low-dose interleukin-2 (ld-IL-2) during the preclinical *** with undifferentiated arthritis (UA), early RA (Ea-RA), new-onset RA (New-RA), and recurrent RA (Re-RA) were included. Clinical data and laboratory parameters were collected from all participants. A comparative analysis of arthritis-related clinical features and serum levels of IL-2 and soluble IL-2 receptor (sIL-2R) was conducted. Collagen-induced arthritis (CIA) mice received ld-IL-2 on days 0, 7, 14, and 28 after primary immunisation for 4 weeks. The percentages of Treg, Tfr, Tfh, and PD-1+Tfh cells were analysed. Additionally, naive CD4+ T cells were cultured in vitro to assess the effects of IL-2 on Tfh and Tfr *** patients primarily exhibited early involvement of large joints. The sIL-2R level in UA patients was significantly lower than in those with Ea-RA, New-RA, and Re-RA and was comparable to levels in healthy controls. ld-IL-2 administration at different time points in the CIA model exerted varying effects on arthritis severity. Prophylactic ld-IL-2 administration reduced arthritis severity and incidence in CIA;it decreased the percentage of PD-1+Tfh cells while increasing Tfr cells, thereby restoring immune balance. All IL-2 intervention groups effectively reduced the Tfh/Tfr ratio and altered the distribution of B cell subsets. Mechanistically, ld-IL-2 primarily suppressed the differentiation of PD-1+Tfh cells and promoted Treg cell differentiation via STAT3 and STAT5 signalling, contributing to the restoration of immune *** findings indicate that elevated sIL-2R levels in UA patients may predict progression to Ea-RA. Furthermore, ld-IL-2 restores immune tolerance by rebalancing Tfh/Tfr populations, highlighting its potential as a novel immunoregulatory strategy during the preclinical pha

关键词： Kisspeptin-10   Osteoarthritis   p53   senescence   SIRT1  

摘要： In Osteoarthritis (OA), the senescence of chondrocytes plays a pivotal role, contributing to cartilage degradation and impairing tissue repair mechanisms. (Kp-10), a peptide hormone, exerts diverse biological functions across multiple cell types and tissues via its receptor Gpr54. However, its role in chondrocytes and OA has been understudied. This study investigates the role of Kp-10 in mitigating TNF-alpha- induced senescence in primary chondrocytes, a hallmark of OA pathogenesis. Gpr54 expression was confirmed in both primary chondrocytes and the ATDC5 chondrogenic cell line, with TNF-alpha treatment leading to a dose-dependent decrease in Gpr54 expression. Kp-10 treatment at concentrations of 50 and 100 nM effectively ameliorated TNF-alpha-induced senescence, as evidenced by diminished senescence-associated beta-galactosidase staining and enhanced telomerase activity. Moreover, Kisspeptin-10 modulated the expression of key regulators involved in cellular aging, including hTERT and TERF2, and suppressed the activation of the p53/p21 pathway. Notably, Kp-10 restored SIRT1 expression, which was downregulated by TNF-alpha. Silencing SIRT1 abolished the protective effects of Kp-10, highlighting the essential role of SIRT1 in its anti-senescence action. These findings suggest that Kp-10 may be a promising therapeutic strategy for OA by mitigating chondrocyte senescence and improving cellular function by modulating the SIRT1 and p53/p21 pathways.

关键词： anti-citrullinated peptide antibody (ACPA)   HLA-DRB1/DQB1   rheumatoid arthritis   treatment response  

摘要： The present study aimed to determine the association of HLA-DRB1/-DQB1 alleles with response to treatment and anti-citrullinated peptide antibody (ACPA) status in Iranian rheumatoid arthritis (RA) patients. A total of 167 RA patients, including 114 good responders (GRs) and 53 poor responders (PRs) as well as 330 ethnic-matched healthy controls, participated in this study. Disease activity and treatment response were assessed using the Disease Activity Score 28-joint (DAS28) scores during the 9-month post-treatment. HLA-DRB1/-DQB1 alleles were identified using polymerase chain reaction with a sequence-specific primers (PCR-SSP) method and compared between the study groups. Of the patients, 106 (63.5%) were ACPA-positive, 88 (52.7%) human leucocyte antigen (HLA)-shared epitope (SE)-positive, 64 (38.3%) ACPA+SE+ and 37 (22.2%) ACPA-SE-. HLA-SE alleles were significantly more frequent in patients (p = 3.2e - 05), in PR versus GR patients (p = 0.01) and in ACPA+ versus ACPA- patients (p = 0.009). PR patients had a higher prevalence of ACPA+SE+ compared to GR patients (p = 0.02). Higher frequencies of DRB1*04:02 (pc = 0.03), *04:04 (pc = 0.007), *04:05 (pc = 5.0e - 05), *10:01 (pc = 1.0e - 04), DQB1*03:02 (pc = 0.002) and *05:01 (pc = 0.002) alleles, and lower frequencies of DRB1*04:01 (pc = 0.007), *11:01 (pc = 0.03), *13:01 (pc = 0.03) and DQB1*06:03 (pc = 0.03) alleles were observed in patients compared to healthy controls. These findings suggest a relationship between HLA-SE alleles and ACPA development and a potential link between HLA-SE/non-SE alleles and therapeutic responses in RA patients.

关键词： Axial spondyloarthritis   Early treatment   Early diagnosis   Giant cell arteritis   IL-17A   IL-17A inhibition   Polymyalgia rheumatica   Psoriasis   Psoriatic arthritis   Rheumatic and musculoskeletal diseases  

摘要： Interleukin-17A (IL-17A) plays a pivotal role in many rheumatic immune-mediated inflammatory diseases. Targeting the IL-17 pathway has transformed the way psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are managed, with a number of IL-17A inhibitors now available for treating rheumatic and musculoskeletal diseases. This narrative review will describe the opportunities presented by novel imaging techniques in understanding the metabolic and mechanical changes that characterize the pathogenesis of PsA and axSpA. It will look at the current consensus definitions of early disease in PsA and axSpA, present evidence for the benefit of early treatment, and highlight the gaps in current knowledge. Finally, it will describe novel treatment targets to address the unmet needs in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) and discuss the potential role of IL-17A inhibition in treating GCA and PMR.