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关键词： Gout   CPPD   Crystal   Interleukin 6   Tocilizumab  

摘要： Gout and calcium pyrophosphate deposition disease (CPPD) are two highly prevalent causes of inflammatory arthritis, characterized by the pathological deposition of monosodium urate (MSU) and CPP crystals, respectively, in joint tissues. These crystals can induce an intense inflammatory response, known as crystal-induced inflammation, which involves innate immunity and is highly dependent of the activation of interleukin 13 (IL-1[3) following the recruitment ofthe NLRP3 inflammasome. In patients in whom first-line treatments (colchicine, prednisone, NSAIDs) are either ineffective or inappropriate, IL-1 inhibitors can be used to treat acute crystal-induced arthritis. However, some patients do not respond to these therapies, or experience adverse events. There is therefore a need for other treatments, particularly in CPPD, where the inflammation induced by CPP crystals can be chronic and affect elderly patients, making IL-1 inhibitors a less suitable option. IL-6, which is highly expressed during crystal-induced inflammation, is emerging as a promising therapeutic target in chronic CPP arthritis, with publications reporting the efficacy of tocilizumab in patients with inadequate response to other treatments, including anakinra, the most commonly used IL-1 inhibitor in this indication (off-label). These data require confirmation in randomized controlled trials. Other therapies, such as JAK inhibitors or NLRP3 inhibitors, may also be of interest in crystal-induced arthritis. (c) 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Societe Franc,aise de Rhumatologie. This is an open access article under the CC BY license (http://***/ licenses/by/4.0/).

关键词： Peptides   Artificial neural networks   HLA-I alleles   IFN-gamma   CD107a  

摘要： Toxoplasma gondii infects approximately 30% of the population, and there is currently no approved vaccine. Identifying immunogenic peptides with high affinity to different HLA molecules is a promising vaccine strategy. This study used an in silico approach using artificial neural networks to identify T. gondii peptides restricted to HLA-A*02, HLA-A*24, and HLA-B*35 alleles. Proteomes from seven T. gondii strains and transcriptomic data of overexpressed genes from T. gondii-RH in human PBMC were also used. Parasite protein sequences were analyzed with R 'Epitope Prediction' library. Peptide candidates were evaluated in the artificial neural networks based on the probabilities of output neurons (p > 0.5). The IFN-gamma responses in PBMC from T. gondii seronegative and seropositive individuals were evaluated by ELISpot. Peptides with higher IFN-gamma induction were evaluated to identify cytotoxic response in CD8+ T cells (CD107a). In silico analysis identified 36 peptides from T. gondii proteins with predicted affinity to HLA-A*02, A*24, and B*35 alleles. Experiments with PBMCs revealed that a peptide restricted to HLA-A02 (P1: FLFAWITYV) induced a significant increase in IFN-gamma-producing cells (p = 0.004). For HLA-A24, a peptide (P8: VFAFAFAFFLI) also induced a significant IFN-gamma response (p = 0.004), while for the HLA-B*35 allele, the P6 peptide (YPIAPSFAM) induced a response that differed significantly from the control (p = 0.05). These peptides induced also a significant percentage of central memory CD8 + T cells expressing the degranulation marker CD107a (p < 0.05). Finally, we identified three T. gondii peptides that induced IFN-gamma response, and a cytotoxic response measured by CD107a expression on CD45RAneg-CD8 cells. These peptides could be considered part of a multi-epitope vaccine against toxoplasmosis in humans.

关键词： Anti-cytokine autoantibodies   Phenocopy   Secondary immunodeficiency   Wound healing  

关键词： Chikungunya virus   Chikungunya fever   Cytokine storm   Signatures   Proinflammatory response  

摘要： Introduction The present study aimed at evaluating the systemic profile and network connectivity of immune mediators during acute chikungunya fever (CHIKF) according to days of symptoms onset and ageing. Methods A total of 161 volunteers (76 CHIKF patients and 85 non-infected healthy controls) were enrolled. Results and discussion Data demonstrated that a massive and polyfunctional storm of serum immune mediators was observed in CHIKF. Distinct patterns of mediators were observed according to days of symptoms onset. Most chemokines and proinflammatory cytokines were increased early at D0-1, with some increased throughout the kinetics timeline, while others presented a waning profile towards D4-12. Rhythmic signatures further underscored these findings. Increased levels IL-17 appeared as a hallmark of intense arthralgia, while CCL5&IL-5 and TNF-alpha&IL-10 duets are age-tunning features in CHIKF. Differential connectivity of networks was observed with ageing, with a progressive increase in the overall connectivity from < 8 yo towards 51-89 yo. Of note, subsets of immune mediators (IL-17, IL-2 and IL-5) displayed hotspots of hyperconnectivity in elderly as compared to younger patients. Conclusion Together, the overall scenario reveals unique patterns of soluble immune mediators during acute CHIKF infection with an oscillating symphony according to days of symptoms and ageing, which brings insight to future tailor-made therapeutic interventions.

关键词： Major histocompatibility complex   SXY module   RFX5 gene   Whole exome sequencing  

摘要： The major histocompatibility complex (MHC) encompasses a group of genes critical for immune system regulation. In humans, these molecules are referred to as human leukocyte antigens (HLA) due to their initial discovery in human leukocytes. Class I molecules present antigens to CD8 + T cells, while Class II molecules present to CD4 + T cells. Here we report a patient who had a background of parental consanguinity and a family history suggestive of immunodeficiency. He presented with clinical symptoms including fever, septic arthritis, recurrent moniliasis. Preliminary diagnostic tests revealed hypogammaglobulinemia and CD4 lymphopenia. Further immunological assessment indicated extremely low expression levels of HLA molecules: HLA ABC at 5% and HLA DR at 0%. Genetic analysis showed a mutation in the regulatory factor X5 (RFX5) gene, leading to a combined immunodeficiency diagnosis. Consequently, hematopoietic stem cell transplantation (HSCT) was planned. Regulatory factor X5plays a pivotal role in immune function by transactivating genes critical for the expression of MHC Class I and Class II molecules, as well as beta- 2-microglobulin (B2M). MHC Class I transcription is controlled indirectly by RFX5, and the RFX5 gene mutation in the patient likely caused the markedly reduced expression of HLA ABC in addition to HLA DR. Combined HLA-ABC and HLA-DR expression analyses via flow cytometry may serve as a valuable diagnostic tool for identifying RFX5-related immunodeficiency at an early stage, facilitating timely genetic testing and appropriate clinical management.

关键词： 4-BOP   IL-35   JAK1/STAT3   Ca2   Phagosome-lysosome fusion   Mycobacteria  

摘要： Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis (TB), modulates host immune responses by regulating various cytokines. Precise regulation of these cytokines renders the host pathogen-free, whereas their dysregulation increases the susceptibility to infection. Hence, induction of host protective cytokines using immunomodulators to promote M. tuberculosis clearance has a rewarding impact in the context of TB treatment. This study explored the immunomodulatory activity of 4-(Benzyloxy)phenol (4-BOP) in mycobacteria infected differentiated THP-1 cells through IL-35 (an anti-inflammatory cytokine) production. Initially, we observed an increased mRNA and protein level expression of IL-35 and its cognate receptor upon 4-BOP treatment in mycobacteria-infected dTHP-1 cells. IL-35 receptor activation further led to phosphorylation of JAK1/STAT3, culminating in increased phagosome-lysosome fusion through elevation of intracellular Ca2+ level. Blocking IL-35 receptors using siRNA-mediated approach against IL-12R beta 2 and gp130 or the JAK1/STAT3 associated signaling with specific inhibitors like Baricitinib and Stattic promoted the intracellular mycobacterial survival by compromising Ca2+-phagosome-lysosome fusion pathway. Further, we identified a direct regulatory role of p53 (known to be activated by 4-BOP) on IL-35 production, and inhibition of p53 using PFT-alpha surprisingly abrogated the IL-35 mediated signaling axis. Collectively, our results demonstrated a host defensive role of 4-BOP-induced Il-35 signaling in mycobacteria-infected dTHP-1 cells through the JAK1/STAT3 mediated Ca2+-phagosome-lysosome fusion pathway. These results suggest that 4-BOP may serve as a potent HDT candidate for regulating inflammation and enhancing host defense in TB infection.

关键词： Spinal cord injury   Collagen hydrogel   bFGF   IL-10   Microspheres  

摘要： Traumatic spinal cord injury (TSCI) is a severe event within the central nervous system, leading to the impairment of sensory and motor abilities at the injury site in the spinal cord. Current therapeutic approaches offer limited efficacy in improving recovery, underscoring the need to explore alternative treatments. In the present study, we examined the sustained co-delivery of basic fibroblast growth factor (bFGF) and interleukin-10 (IL-10), encapsulated in microspheres and incorporated into a collagen-based hydrogel, for its effects on the healing of TSCI in an animal model. Seventy-five male Sprague Dawley rats were randomly divided into five groups: control, TSCI, hydrogel, microspheres, and hydrogel loaded with microspheres (Hyd + Micro). Tissue samples were collected from the injury site for further evaluation. Compared to the TSCI group, treatment groups demonstrated notably higher numerical densities of neurons and greater motor neuron health, as well as increased levels of vascular endothelial growth factor (VEGF) and antioxidative factors (catalase [CAT], glutathione [GSH], and superoxide dismutase [SOD]), and improved neurological function scores (electromyography [EMG], Basso-Beattie-Bresnahan (BBB) test, and narrow beam-walking test [NBT]). These changes were most pronounced in the Hyd + Micro group. The treatment also led to a significant decrease in the counts of apoptotic and glial cells, alongside reduced levels of malondialdehyde (MDA) and pro-inflammatory cytokines (IL-1 beta and TNF-alpha), with the most notable enhancements seen in the Hyd + Micro group. These findings indicate that the co-delivery of bFGF and IL-10 encapsulated in microspheres within a collagen-based hydrogel provides enhanced neuroprotective effects in TSCI animal models.

关键词： Allergic rhinitis   Follicular regulatory T cells   Type 2 follicular helper T   Interleukin-35  

摘要： BackgroundAllergic rhinitis (AR) represents a persistent inflammatory condition affecting the upper respiratory tract, characterized by abnormal initiation of the immunoglobulin E (IgE)-mediated cascade. Follicular helper T (Tfh) cells and regulatory T (Tfr) cells are pivotal in orchestrating the development of IgE production in AR patients. IL-35, an anti-inflammatory cytokine, secreted by various cellular *** investigate the interplay and underlying mechanisms between interleukin-35 (IL-35) and Tfr/Tfh2 cells in the context of *** animal models employing BALB/c mice and IL-35-deficient mice underwent sensitization and challenge procedures utilizing ovalbumin (OVA) as the antigen in vivo. IL-35 was administered intranasally prior to OVA challenges. Nasal histopathological examination, PBMC isolation, Tfr/Tfh2 cell staining, Tfr/Tfh2 sorting and culture, and qPCR analysis as well as enzyme-linked immunosorbent assay (ELISA) were conducted for exploring the effect of IL-35 on Tfr/Tfh2 *** of IL-35 suppressed OVA-elicited allergic inflammation in murine models. IL-35 treatment led to an elevation in the proportion of peripheral blood Tfr cells and a decrease in Tfh2 cells. IL-35 also downregulated IL-4 and IL-21 protein expression by Tfh2 cells and upregulated IL-10 and transforming growth factor-beta (TGF-beta) production by Tfr cells. The anti-ICOS treatment abrogated the effect of IL-35 on Tfh2 and Tfr *** study provided novel insights into the mechanisms of IL-35 action and its promoting effects on Tfh2 and inhibiting effects on Tfr cells by targeting key transcription factors, contributing to the understanding of the pathogenesis and treatment of AR.

关键词： Type one diabetes mellitus   HLA-DQA1   HLA-DQB1   CTLA-4  

摘要： Background Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the selective destruction of pancreatic beta cells, leading to insulin deficiency. Both genetic and environmental factors contribute to disease susceptibility. Among genetic factors, human leukocyte antigen (HLA) class II molecules, particulary DQA1 and DQB1 haplotypes, have been associated with T1D risk. This study aimed to identify haplotypes that increase susceptibility to or provide protection against T1D in Jordanian population. Methods A total of 200 healthy individuals and 200 T1D patients were included in the study. Genomic DNA was extracted from blood samples and HLA-DQA1, HLA-DQB1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) gene regions were amplified by PCR. The PCR products were then subjected to restriction enzyme digestion and analyzed through agarose gel electrophoresis to determine different haplotypes. Results Among the analyzed haplotypes, HLA-DQA1*01:01 was found to be significantly associated with increased susceptibility to T1D. In contrast, HLA-DQA1*02:01 and HLA-DQB1*05:01 appeared to provide protective effects against T1D. No significant differences were observed for other haplotypes between the control and patient groups. Additionally, no significant difference has been observed in terms of CTLA-4 polymorphisms. Conclusion These findings suggest that HLA-DQA1*01:01 may serve as a genetic marker for T1D susceptibility, while HLA-DQA1*02:01 and HLA-DQB1*05:01 may confer protectionin the Jordanian population. Identifying these genetic risk factors could contribute to early disease prevention strategies and advanced research into additional genetic markers associated with T1D.