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关键词： Autoantibodies targeting the IL-36 receptor   antagonist (IL-36Ra) occur in subgroups of patients with PsA and Pso   IL-36Ra-autoantibodies deplete IL-36Ra   serum/plasma level   result in immunecomplex   formation   and promote unrestricted IL-36   signal  

摘要： Objective: Psoriatic arthritis (PsA) is known as a seronegative form of spondylarthropathy. The interleukin-36 cytokine family may have a major role in disease pathogenesis and particularly the related cutaneous manifestations. In light of our recent observations on (transient) autoantibody phenotypes neutralizing endogenous anti-inflammatory receptor antagonists (progranulin, IL-1Ra) in different inflammatory conditions, we set out to investigate the potential role of such antibodies targeting IL-36 cytokine family members in PsA and psoriasis without arthritic manifestations (Pso). Methods: In the present study we screened for hypothetic autoantibodies against the anti-inflammatory mediators IL-36 receptor antagonist (IL-36Ra) and anti-inflammatory IL-38 in PsA, Pso and inflammatory and healthy controls. Serum samples of patients with PsA (n n = 254), Pso (n n = 100), systemic lupus erythematosus (SLE, n = 50), rheumatoid arthritis (RA, n =100), ulcerative colitis (UC, n = 50), Crohns disease (CD, n = 50), and healthy controls (n n = 237) were screened for autoantibodies against IL-36Ra and IL-38 as well as IL-36Ra levels by ELISA. Biochemical analysis for immune complexes and atypic protein isoforms as well as IL-36 signaling reporter assays were performed. Results: Anti-IL-36Ra antibodies were detected in five out of 100 (5.0 %) patients with Pso, in 12 of 254 (4.72 %) patients with PsA and in one of 50 (2 %) patients with CD, but in none of the other investigated inflammatory or healthy controls. The IL-36Ra autoantibodies belonged to the IgG1 subclass and their titers ranged between 1:200 to 1:1600. They resulted in immune-complex formation, depletion of serum IL-36Ra levels and were functional in terms of facilitating unrestricted IL-36 signaling. Conclusion: IL-36Ra autoantibodies were found in subgroups of patients with Pso and PsA and may drive respective pathology.

关键词： exosome   HLA-E   lung cancer   macrophage   transcription factor  

摘要： Immunotherapy is a pivotal approach in the treatment of lung cancer. Although HLA-E is a potential target for tumor immunotherapy, its role in lung cancer remains unclear. Previous studies have identified the transcription factor IRF5 as a characteristic gene of M1-like macrophages, highlighting its crucial role in promoting antitumor immune responses. In this study, we developed an engineered M1-like macrophage exosomes expressing IRF5 (IRF5 M1-exos) and demonstrated their ability to inhibit proliferation, migration, and invasion of lung cancer cells. Moreover, our experiments using a nude mouse model revealed that IRF5 M1-exos exerted potent therapeutic effects by effectively suppressing tumor growth. Notably, the mechanism by which IRF5 exerts its antitumor function through HLA-E regulation in lung cancer has not been fully elucidated. Here, we identified HLA-E as a downstream target gene of IRF5 and demonstrated that the overexpression of HLA-E can counteract the tumor-promoting effects induced by si-IRF5 M1-exos. These results suggest that M1 macrophage-derived exosomes, enriched with the transcription factor IRF5, exhibit potent antitumor activity by up-regulating HLA-E in lung cancer cells. Therefore, IRF5 M1-exos represent an attractive therapeutic strategy for lung cancer.

关键词： Atopic dermatitis   IL-4   dendritic cells   T H2 cell polarization  

关键词： HLA-B*48:01:14   novel allele   sequencing-based typing  

摘要： Identification of the novel HLA-B*48:01:14 allele, which differs from HLA-B*48:01:01 at one position.

关键词： intervertebral disc degeneration   TNF receptor   tumor necrosis factor-alpha  

摘要： BackgroundIntervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), worsened by chronic inflammatory processes associated with aging. Tumor necrosis factor alpha (Tnf-alpha) and its receptors, Tnf receptor type 1 (Tnfr1) and Tnf receptor type 2 (Tnfr2), are upregulated in IVDD. However, its pathologic mechanisms remain poorly *** investigate the role of Tnfr in IVDD, we generated global Tnfr1/2 double knockout (KO) mice and age-matched control C57BL/6 male mice, and analyzed intervertebral disc (IVD)-related phenotypes of both genotypes under physiological conditions, aging, and lumbar spine instability (LSI) model through histological and immunofluorescence analyses and mu CT imaging. Expression levels of key extracellular matrix (ECM) proteins in aged and LSI mice, especially markers of cell proliferation and apoptosis, were evaluated in aged (21-month-old) *** 4 months, KO and control mice showed no marked differences of IVDD-related parameters. However, at 21 months of age, the loss of Tnfr expression significantly alleviated IVDD-like phenotypes, including a significant increase in height of the nucleus pulposus (NPs) and reductions of endplates (EPs) porosity and histopathological scores, when compared to controls. Tnfr deficiency promoted anabolic metabolism of the ECM proteins and suppressed ECM catabolism. Tnfr loss largely inhibited hypertrophic differentiation, and, in the meantime, suppressed cell apoptosis and cellular senescence in the annulus fibrosis, NP, and EP tissues without affecting cell proliferation. Similar results were observed in the LSI model, where Tnfr deficiency significantly alleviated IVDD and enhanced ECM anabolic metabolism while suppressing *** deletion of Tnfr mitigates age-related and LSI-induced IVDD, as evidenced by preserved IVD structure, and improved ECM integrity. These findings suggest a crucial role of Tnf-alpha/Tnfr signaling in IVDD pathogenesis in mic

关键词： Multiple sclerosis   Cuprizone   Spinal cord   Zinc   ZnT3   IL-6   Oxidative stress  

摘要： The aim of this study was to investigate the effects of dietary zinc status on spinal cord tissue damage and ZnT3, IL-6 gene expressions in a cuprizone-induced rat Multiple Sclerosis (MS) model. The study was carried out on 46 adult male rats of the genus Wistar. The animals used in the study were divided into 5 groups (G) (Control 6, other groups 10). G1, Control. G2, Sham-MS: Carboxy-methyl-cellulose (KMS) solution in which Cuprizon was dissolved was given to rats by gavage daily for 8 weeks at the rate of 1 % of daily feed consumption. MS was formed by giving 1 % of the daily feed consumption cuprizon in KMS solution by gavage to the animals in G3, 4 and 5 for 8 weeks. G4 was fed with a zinc deficient (50 mu g/kg zinc) diet. G5 was given intraperitoneal (ip) zinc sulfate (5 mg/kg/day) supplementation. MS formation in animals was determined by Rotarod tests and Myelin Basic Protein (MBP) gene expression analysis. ZNT3 and IL-6 gene expression levels in spinal cord tissue samples of animals by Real-Time-PCR method;MDA and GSH levels were determined by ELISA method. The highest spinal cord MDA and IL-6 levels were obtained in G3 and G4 (P<0.05). Zinc supplementation in G5 prevented the increase in the mentioned parameters and turned them into control values (P<0.05). The spinal cord GSH and ZnT3 levels of G3 and G4 were lower than all other groups (P<0.05). Zinc supplementation prevented suppression in the same parameters in G5 and reached the control values (P<0.05). The findings of the current study suggest that zinc supplementation in addition to treatment for MS may be beneficial in reducing the severity of the disease.

关键词： DQB1*02:02:01:14   HLA   new allele   pseudo-exon  

摘要： The novel allele HLA-DQB1*02:02:01:14 differs from HLA-DQB1*02:02:01:01 by one nucleotide substitution in codon 233 in exon 5.

摘要： Since most genetically modified mice are C57BL/6 background, a mouse-adapted SARS-CoV-2 that causes lethal infection in young C57BL/6 mice is useful for studying innate immune protection against SARS-CoV-2 infection. Here, we established two mouse-adapted SARS-CoV-2, ancestral and Delta variants, by serial passaging 80 times in C57BL/6 mice. Although young C57BL/6 mice were resistant to infection with the mouse-adapted ancestral SARS-CoV-2, the mouse-adapted SARS-CoV-2 Delta variant caused lethal infection in young C57BL/6 mice. In contrast, MyD88 and IFNAR1 KO mice exhibited resistance to lethal infection with the mouse-adapted SARS-CoV-2 Delta variant. Treatment with recombinant IFN-alpha/beta at the time of infection protected mice from lethal infection with the mouse-adapted SARS-CoV-2 Delta variant, but intranasal administration of recombinant IFN-alpha/beta at 2 days post infection exacerbated the disease severity following the mouse-adapted ancestral SARS-CoV-2 infection. Moreover, we showed that TNF-alpha amplified by type I IFN signals exacerbated the SARS-CoV-2 infection by stimulating CXCL1 production from macrophages and neutrophil recruitment into the lung tissue. Finally, we showed that intravenous administration to mice or hamsters with TNF protease inhibitor 2 alleviated the severity of SARS-CoV-2 and influenza virus infection. Our results uncover an unexpected mechanism by which type I interferon-mediated TNF-alpha signaling exacerbates the disease severity and will aid in the development of novel therapeutic strategies to treat respiratory virus infection and associated diseases such as influenza and COVID-19.

关键词： Interleukin-27   IL-27RA   POI   Macrophages   Obesity   Lipids  

摘要： Premature ovarian insufficiency (POI) critically affects female reproductive health, with obesity being a significant and recognized risk factor. Interleukin-27 (IL-27), known for its role in immune modulation and inflammation, has garnered attention in metabolic syndrome research. Nonetheless, the role of these immunometabolic factors on the initiation of POI remains to be unraveled. Our investigation delves into the influence of impaired IL-27 signaling on POI induction, particularly under the challenge of a high-fat diet (HFD). We analyzed patients' serum profiles and established a correlation of increased serum triglycerides with decreased IL-27 levels in POI cases. Experiments on C57BL/6 mice lacking the IL-27 receptor alpha (Il27ra- /- ) revealed that when subjected to HFD, these mice developed hallmark POI symptoms. This includes escalated lipid deposition in both liver and ovarian tissues, increased ovarian macrophages cellular aging, and diminished follicle count, all pointing to compromised ovarian function. These findings unveil a novel pathway wherein impaired IL-27 signaling potentiates the onset of POI in the presence of HFD. Understanding the intricate interplay between IL-27, metabolic alterations, and immune dysregulation sheds light on potential therapeutic avenues for managing POI, offering hope for improved reproductive health outcomes.