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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： Autoimmune myocarditis   Hydrogen   Necroptosis   TNF/TNFR1 signalling   CD4+T cell  

摘要： Autoimmune myocarditis refers to the inflammation of myocardial tissue caused by innate and adaptive immune responses, characterized by elevated levels of tumour necrosis factor-alpha (TNF-alpha), a classic pro-inflammatory factor. Although hydrogen exhibits anti-inflammatory and antioxidant properties, its therapeutic effects in autoimmune myocarditis have not been evaluated. Therefore, the present study aimed to explore whether hydrogen can alleviate autoimmune myocarditis via TNF-alpha. An experimental autoimmune myocarditis (EAM) model was established in BALB/c mice via subcutaneous injection of pig-derived myocardial myoglobin emulsified with complete Freund's adjuvant. The treatment group received 2 % hydrogen inhalation twice a day (3 h each time) for 21 days. CD4+ T cell expression was higher in the EAM group than in the Control group, and this increase was attenuated following treatment with hydrogen. Additionally, the levels of TNF-alpha and related inflammatory factors were substantially higher in the EAM group than in the Control group, and these changes were reversed following hydrogen treatment. Echocardiography assessments demonstrated a significant improvement in heart function following treatment with hydrogen compared to that in the EAM group. Pathological results revealed significant inflammatory cell infiltration and fibrosis in the hearts of the untreated EAM group. Tissue immunofluorescence and protein immunoblotting indicated elevated necroptosis markers in the EAM group, which were downregulated after treatment with hydrogen. This study demonstrates that hydrogen effectively ameliorated autoimmune myocarditis by modulating necroptosis via the TNF/TNFR1 signalling pathway, making it a promising novel therapeutic strategy for myocarditis.

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： 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： 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： 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.

关键词： HLA genotype   T cell donors   BK virus   Virus-specific T cells  

摘要： PurposeThe increasing application of virus-specific T cell therapy for treating BK virus infections in immunocompromised patients highlights the necessity for rapid identification of compatible cell donors with optimal BK-specific T cell response. This study aims to characterize the BK virus-specific T cell response in relation to demographic factors, blood group, serological status, and HLA genotypes using samples from a cell donor *** blood mononuclear cells from cell donors were stimulated with peptide pools derived from VP1 and LTA proteins, and the IFN-gamma production was analyzed using ELISpot and validated by flow *** findings provide an overview of the T cell response to BK virus proteins in healthy donors, revealing associations with demographic characteristics, RhD status, CMV or EBV serological status, and HLA alleles. Remarkably, RhD-negative, CMV-seronegative, and EBV-seronegative donors showed a major T cell response against BK virus proteins. Notably, certain HLA alleles were associated with either enhanced or diminished T cell response. Furthermore, our results suggest that HLA-B leader dimorphism, specifically the presence of threonine at position 2, influences the VP1-specific immune response, resulting in enhanced T cell *** study, beyond advancing our understanding of the relationship between donor characteristics and BK virus-specific T cell response, has significant implications for improving the selection of optimal cell donors for patient-specific adoptive therapy.

关键词： Vitiligo   Chronic unpredictable mild stress (CUMS)   Fibroblasts   Cellular senescence   IL-6  

摘要： BackgroundPsychological stress is the most common psychological comorbidity and a significant triggering factor of vitiligo. Moderate to severe psychological stress can markedly affect the efficacy of vitiligo treatment. However, the specific mechanisms underlying its involvement remain insufficiently *** unpredictable mild stress (CUMS)-induced major depressive disorder (MDD)-like behavior was modeled in C57BL/6 mice alongside wild-type mice to investigate differences in vitiligo pathogenesis. White spot tissues from mouse tails were subjected to high-throughput transcriptomic sequencing (RNA-seq). In vitro experiments utilized beta-galactosidase, P16, and P21 to assess IFN-gamma-induced senescence. The effects of exogenous IL-6 on fibroblast senescence were assessed, and the role of blocking the IL-6 autocrine loop with an IL-6R inhibitor in reversing IFN-gamma-induced fibroblast senescence was ***-induced MDD -like mice exhibited significantly lower body mass index and sugar-water preference index compared to wild-type mice, and their vitiligo severity was markedly increased. Transcriptomic sequencing revealed significant upregulation of cellular senescence and JAK-STAT signaling pathways in white spot tissues of depressive-like vitiligo mice. In vitro findings indicated that IFN-gamma induced fibroblast senescence via activation of the JAK2-STAT3 signaling pathway, which subsequently promoted melanocyte apoptosis and increased IL-6 secretion and IL-6R expression. Exogenous IL-6 further activated the JAK2-STAT3 signaling pathway, induced fibroblast senescence, and synergistically intensified IFN-gamma-induced fibroblast *** activation of the IL-6 autocrine loop, synergizing with IFN-gamma to aggravate fibroblast senescence and promote melanocyte apoptosis. Blocking the IL-6 autocrine loop may serve as an effective approach to mitigate the impact of CUMS on vitiligo pathogenesis and treatment efficacy

关键词： Aquaporin 1   Rheumatoid arthritis   Autophagy   Apoptosis   Proliferation   Fibroblast-like synoviocytes  

摘要： Objective Fibroblast-like synoviocytes (FLS) are key players in rheumatoid arthritis (RA) by resisting apoptosis via increased autophagy. Elevated synovial aquaporin 1 (AQP1) affects RA FLS behaviors, but its relationship with FLS autophagy is unclear. We aim to clarify that silencing AQP1 inhibits autophagy to exert its anti-RA effects. Methods We studied the effects and mechanisms of AQP1 silencing on autophagy in TNF-alpha-induced RA FLS and examined the crucial role of autophagy inhibition in its impacts on RA FLS pathogenic behaviors. We explored whether silencing synovial AQP1 relieved rat adjuvant-induced arthritis (AIA) by reducing synovial autophagy. Results TNF-alpha stimulation increased AQP1 expression and autophagy levels in RA FLS, with a positive correlation between them. AQP1 silencing inhibited autophagy in TNF-alpha-stimulated RA FLS, along with suppressing proliferation, promoting apoptosis, and mitigating inflammation. Notably, the inhibitory effects of AQP1 silencing on RA FLS pathogenic behaviors were cancelled by autophagy activation with rapamycin (Rapa) but enhanced by autophagy inhibition using 3-Methyladenine. Mechanistically, silencing AQP1 enhanced the binding of Bcl-2 to Beclin1 by decreasing Beclin1-K63 ubiquitination, thus inhibiting RA FLS autophagy. In vivo, silencing synovial AQP1 relieved the severity and development of rat AIA, alongside reducing Ki67 expression, promoting apoptosis, and decreasing autophagy within AIA rat synovium. Expectedly, the Rapa co-administration nullified the anti-AIA effects of silencing synovial AQP1. Conclusion These findings reveal that silencing AQP1 inhibits RA FLS pathogenic behaviors and attenuates rat AIA through autophagy inhibition. This study may help clarify the pathogenic role of AQP1 in enhancing autophagy during RA development.