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关键词： HLA   HLA-C*07:1187   novel allele   sequencing-based typing  

摘要： HLA-C*07:1187 differs from HLA-C*07:02:01:01 by one nucleotide substitution in codon 304 in exon 5.

关键词： biologic therapy   dual biologic therapy   dupilumab   atopic dermatitis   psoriasis   psoriatic arthritis   inflammatory bowel disease   rheumatoid arthritis   TNF-alpha inhibitors  

关键词： Anti-IL-5 monoclonal antibody therapy   Meta-anal-ysis   Infectious diseases   Pneumonia   Sinusitis   Influenza   Clos-tridium difficile infection  

摘要： BACKGROUND: Although multiple meta-analyses have evaluated the efficacy and safety of anti-IL-5 mAb therapy, few studies have made detailed, specific assessments of adverse events and infectious disease (ID) adverse events. OBJECTIVE: To conduct a meta-analysis to evaluate the effect of anti-IL-5 therapy on ID adverse events. METHODS: We undertook a meta-analysis using 27 randomized, placebo-controlled phase 3 clinical trials. Detailed information on ID events was extracted, as well as study demographics. We recorded ID events as serious events and non serious events as they appeared in the clinical trial record in ***. The ID events were then classified into clinical and microbiologic groups. RESULTS: Anti-IL-5 therapy significantly reduced serious bacterial infections (relative risk [RR] = 0.808;95% CI, 0.667-0.978) and pneumonia (RR = 0.806;95% CI, 0.650-0.998). Anti-IL-5 therapy also significantly reduced influenza infection (RR = 0.817;95% CI, 0.674-0.991), sinusitis (RR = 0.807;95% CI, 0.685-0.951), non-serious lower respiratory tract infections (RR = 0.787;95% CI, 0.656-0.943), and Clostridium difficile infection (P = .025). Non-serious gastroenteritis was increased in patients receiving anti-IL-5 therapy (RR = 1.754;95% CI, 1.087-2.830). CONCLUSIONS: Anti-IL-5 therapy significantly reduces adverse events categorized as serious bacterial infections, pneumonia, influenza, non-serious lower respiratory tract infections, and C difficile infection. In the population of patients receiving anti-IL-5 therapy, these effects may translate into substantial decreases in health care use. (c) 2025 American Academy of Allergy, Asthma & Immunology

关键词： T cell receptor   rheumatoid arthritis   autoimmunity   post-translational modification   MHC  

摘要： CD4+ T cell autoreactivity against citrullinated (cit) selfepitopes presented by HLA-DRB1 is associated with rheumatoid arthritis (RA) pathogenesis. We understand the molecular bases of T cell receptor (TCR) recognition of cit-fibrinogen, cit-vimentin, and cit-a-enolase epitopes, and the role of citrulline in shaping TCR repertoire usage. Nevertheless, how TCRs recognize other cit-epitopes, including tenascin-C (TNC) and how alternative citrullination positions may modulate the T cell recognition remains unclear. Here, we examined TNC1014,1016cit peptide, which contains citrullination at position P-1 and P2, to study the underlying TCR-HLA-DRB1*04:01-TNC1014,1016cit molecular interactions. Crystal structure of HLA-DRB1*04:01TNC1014,1016cit at 2.4 & Aring;resolution revealed a conserved peptide binding register to the established HLA-DRB1*04:01-peptide structures, where both citrullines protruded upward. Next, we determined the crystal structure of a RA patient-derived TRAV35+/TRBV10-2+ (PB) TCR in complex with HLA-DRB1*04:01TNC1014,1016cit at 3.2 & Aring;resolution. The CDR3a loop (109VGNTN113) of PB TCR formed a secondary helical conformation at the N-terminus of the peptide binding cleft, allowing extensive interactions between the P-1 and P2 citrullines of TNC1014,1016cit peptide. Surface plasmon resonance, tetramer staining, and CD69 activation assays revealed that the PB TCR did not cross-react to other RA autoantigens, and the P-1-Cit, P2-Cit, and P5-Tyr of TNC1014,1016cit are the key determinants underlying the strict specificity of the PB TCR. Collectively, we provide molecular insight into citrullination in modulating TCR recognition.

关键词： association study   BoLA   bovine   environmental streptococci   major histocompatibility complex (MHC)   mastitis   NGS   targeted resequencing  

摘要： Mastitis is an inflammatory reaction caused by bacterial infection of the teat, and a relationship between its onset and cattle major histocompatibility complex (BoLA) region has been reported. However, no comprehensive genetic analysis of mastitis caused by environmental streptococci has been reported. Here, we resequenced the BoLA region using a hybridisation capture target next-generation sequencing (NGS) method to identify disease susceptibility markers mapped to the BoLA region in environmental streptococcal mastitis. This study examined 75 cows with mastitis caused by environmental streptococci selected from 1641 cows with mastitis and 222 healthy cows without mastitis in Japan. Targeted sequences obtained from MiSeq NGS were aligned to the bovine reference genome (ARS-UCD1.2/bosTau9), and 2,920,355 variants were detected within the BoLA region of the 297 Holstein cattle. In an association study using 2264 variants after quality control, the top 20 variants with the lowest P values were selected and assigned to the 18 surrounding candidate genes, and a gene network analysis of these genes resulted in the narrowing down of five candidate genes POU5F1, IER3, GNL1, ABCF1, and PRR3. Multivariate effect analysis of all 6 SNPs associated with these 5 genes revealed that they were significantly correlated with mastitis, indicating that they were useful for classification of mastitis-resistant and mastitis-susceptible cattle. This is the first report to identify SNPs associated with environmental streptococcal mastitis with an NGS-based association study using targeted resequencing in the BoLA region, and understanding host factors may provide important clues for mastitis control.

关键词： Osteoarthritis   Interleukin-6   Glycoprotein 130   Signal transducer and activator of transcription   microRNA-146a   3  

摘要： Interleukin-6 (IL-6) is a crucial inflammatory cytokine associated with chronic pain and cartilage degradation in osteoarthritis (OA). The binding of IL-6 to the IL-6 receptor (IL-6R) leads to homodimerization and the recruitment of glycoprotein 130 (gp130), subsequently activating the transcription factor signal transducer and activator of transcription 3 (STAT3) to initiate the downstream inflammatory cascade. Therefore, a therapy that targets the IL-6/IL-6R/STAT3 signaling axis shows promise for OA treatment. MicroRNAs (miRs) modulate messenger RNA in translational regulation, and dysregulation of miR-146a is noted in articular cartilage. In addition, miR-146a is also known to regulate IL-6 expression and affect OA-associated algesia. Bioinformatic analysis revealed that miR-146a-3p targets IL-6, IL-6R, gp130, and STAT3 simultaneously. Accordingly, we hypothesize that multipoint targeting the IL-6/IL-6R/STAT3 signaling axis through intra-articular injection of liposomal miR-146a-3p mimic might replace anti-IL-6 monoclonal antibody therapy and serve as a diseasemodifying treatment for OA.

摘要： *** introduction of posttransplant cyclophosphamide (PTCy) for prophylaxis against graft-versus-host disease (GVHD) has led to an increase in the number of transplants from haploidentical donors. Accordingly, we aimed to understand the impact of HLA epitope mismatch on the outcomes of haploidentical hematopoietic stem cell transplantation (HSCT) with prophylaxis against *** retrospective study included 1037 patients who underwent their first HSCT for hematologic malignancies from haploidentical peripheral blood donors in a Japanese registry between 2011 and 2019. In total, 542 patients received PTCy and 495 received antithymocyte globulin-based GVHD *** patients with high-risk disease who received PTCy, higher class I Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE-I) scores were associated with a significantly lower risk of relapse, leading to a higher overall survival (OS: high PIRCHE-I patients compared with low PIRCHE-I patients: relapse: hazard ratio [HR], 0.67;95% confidence interval [CI], 0.46-0.98;P = 0.040;mortality: HR, 0.69;95% CI, 0.46-0.99;P = 0.042). In patients with standard-risk disease who received antithymocyte globulin, a significant association between class II PIRCHE (PIRCHE-II) and a lower incidence of nonrelapse mortality (NRM) leading to higher OS was observed (high PIRCHE-II patients compared with low PIRCHE-II patients, NRM: HR, 0.41;95% CI, 0.19-0.86;P = 0.019;OS: HR, 0.55;95% CI, 0.32-0.94;P = 0.030).*** findings suggest the differential effects of T-cell epitope matching based on GVHD prophylaxis after haploidentical HSCT. Pretransplant disease status may also be important for understanding the graft-versus-leukemia effect of mismatched HLA in haploidentical HSCT using PTCy.

关键词： cartilage degradation   condylar chondrocytes   DDX5   temporomandibular joint osteoarthritis   tumor necrosis factor signaling  

摘要： Background: Temporomandibular joint osteoarthritis (TMJOA) is a prevalent musculoskeletal condition characterized by pain, cartilage degeneration, and subchondral bone loss. Objective: This study sought to identify specific targets for the treatment of TMJOA. Method: Through high-throughput RNA-seq analysis in condylar chondrocytes (NC vs. MS), we discovered that DDX5 was downregulated and closely negatively related to the progression of TMJOA. Similarly, we found that DDX5 was downregulated in injured condylar cartilage of patients as well as the condyles of UAC-induced TMJOA mice. The chondrocyte-specific deletion of Ddx5 aggravated tissue destruction in TMJOA modeling by inducing degradation of extracellular matrix (ECM). Results: The loss of DDX5 facilitated chondrocyte degradation and the occurrence of joint inflammation in condylar chondrocytes. In addition, the local injection of AAV overexpressing DDX5 significantly alleviated inflammation, cartilage degradation, and subchondral bone loss in TMJOA mice. RNA-seq analysis revealed that the DDX5 deficiency mostly activated the TNF-induced nuclear factor-kappa B (NF-kappa B) signaling pathway causing the occurrence of TMJOA. Conclusion: Mechanistically, the inhibition of DDX5 accelerated cartilage degeneration by activating TNF-induced NF-kappa B signaling. Thus, DDX5 emerges as a potential effective drug target for future therapeutic approaches in TMJOA.

关键词： ankylosing spondylitis   HLA-B27   seasonality   uveitis  

摘要： Background: To examine if there was a monthly variation in HLA-B27-associated uveitis. Methods: Retrospective review of all individuals presenting to a single centre with HLA-B27-associated uveitis from 2009 to 2020. Results: 577 participants with HLA-B27-associated uveitis were included. The median age at presentation was 40.4 years (IQR 31.1-51.4) and 356 (61.7%) were male. 141 (24.4%) participants were diagnosed with ankylosing spondylitis. The incidence of HLA-B27 uveitis was greatest in August (winter) and lowest in March (autumn). On univariate analysis, there was an inverse relationship between HLA-B27-associated uveitis incidence and mean air temperature (beta-2.704, p < 0.001) and sunlight hours (beta-0.221, p = 0.003), and a positive relationship between uveitis incidence and rainfall (beta 0.324, p = 0.006) and humidity (beta 1.741, p = 0.006). On multivariate analysis, there was an inverse relationship with temperature (beta-4.846, p = 0.002) and a positive association with humidity (beta 2.033, p = 0.008). On multivariate analysis, the impact of rainfall shifted to negative (beta-0.446, p = 0.017) and sunlight hours lost significance. The monthly effect was more pronounced for non-Caucasian ethnicities and for those without ankylosing spondylitis. Conclusion: In New Zealand, HLA-B27-associated uveitis episodes are influenced by monthly changes with higher incidence in winter months.

关键词： Psoriatic arthritis   TNF-a inhibitor   Flare   Tapering   Ultrasonography  

摘要： Objective: Dose reduction of biologic drugs in patients with psoriatic arthritis (PsA) who are in Minimal Disease Activity (MDA) is now considered a feasible option. This study evaluated which baseline clinical and ultrasonographic (US) factors may be predictive of disease activity after anti-TNF-a spacing. Methods: This observational, prospective, multicentre, 12-month study enrolled consecutive adult patients with PsA taking TNF-a inhibitors and in stable MDA who accepted to reduce their dose therapy by doubling the administration interval. Data collection included demographics, personal history, clinical disease characteristics, and joints and entheses US features. Patients maintaining the MDA were compared with those who experienced a disease flare during the 12 months of follow-up. The statistical analysis included the comparison between groups and the search of the factors associated with persistence of MDA. Results: Of the evaluable 72 patients (29 females and 43 males), 55 (76.4%) maintained a state of MDA while 17 (23.6%) experienced a disease relapse. Baseline values of DAPSA<2 and of BASDAI<1.5, and lower BASDAI and DAS28 values were significantly associated with maintenance of MDA. The multivariate analysis showed that baseline values of DAPSA< 2 and of BASDAI < 1.5 were predictive of persistence of MDA. Baseline US findings were not associated with the outcome of disease activity. Conclusions: In this study, anti-TNF-a spacing proved to be feasible in most of the PsA patients in a stable MDA. The only factor predictive of persistence of remission was a very low clinical disease activity at baseline. (c) 2025 Socioto Fran oaise de Rhumatologie. Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.