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关键词： AQP9   Crohn's disease   anti-TNF therapy  

摘要： Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1β⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn's disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn's disease.

关键词： IL20Rb   Idiopathic pulmonary fibrosis   Jak2/Stat3   profibrotic macrophages  

摘要： Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

关键词： Autoimmune Diseases   Granulomatosis with polyangiitis   Polymorphism, Genetic   Systemic vasculitis  

摘要： OBJECTIVE:The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. METHODS:Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. RESULTS:PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. CONCLUSIONS:The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the region mediate potentially different functional effects.

关键词： Arthritis, Reactive   Autoimmunity   Spondylitis, Ankylosing   Synovial fluid   T-Lymphocytes  

关键词： CAPSL   CD226   CLEC16A   Graves’ disease (GD)   Hashimoto’s thyroiditis (HT)   Il7R   autoimmune thyroid diseases (AITDs)   children   genetic susceptibility   single-nucleotide polymorphism (SNP)  

摘要： Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, = 0.028) and between all GD patients and healthy children (C > T, = 0.035) as well as GD females and controls (C > T, = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

关键词： 免疫检查点抑制剂相关性肺炎   抗肿瘤免疫治疗   替雷利珠单抗   重症肺炎   细胞因子  

摘要： 免疫治疗是目前抗肿瘤治疗中的热门领域之一，为传统化疗、放疗及靶向治疗效果不佳的患者带来新的希望，其主要通过抑制肿瘤细胞免疫逃逸机制，使患者自身免疫系统对抗肿瘤细胞发挥治疗作用[1]。目前主要的免疫治疗使用免疫检查点对应的抗体即免疫检查点抑制剂(immune checkpoint inhibitor， ICI)，由于抗肿瘤免疫治疗解除了原有的免疫自稳状态，因此治疗后可能导致一些正常的组织细胞亦受到免疫系统攻击，从而出现免疫相关不良反应(immune-related adverse event， irAE)。

摘要： The Major Histocompatibility Complex class I (MHC-I) system plays a vital role in immune responses by presenting antigens to T cells. Allele specific technologies, including recombinant MHC-I technologies, have been extensively used in T cell analyses for COVID-19 patients and are currently used in the development of immunotherapies for cancer. However, the immense diversity of MHC-I alleles presents challenges. The genetic diversity serves as the foundation of personalized medicine, yet it also poses a potential risk of exacerbating healthcare disparities based on MHC-I alleles. To assess potential biases, we analysed (pre)clinical publications focusing on COVID-19 studies and T cell receptor (TCR)-based clinical trials. Our findings reveal an underrepresentation of MHC-I alleles associated with Asian, Australian, and African descent. Ensuring diverse representation is vital for advancing personalized medicine and global healthcare equity, transcending genetic diversity. Addressing this disparity is essential to unlock the full potential of T cells for enhancing diagnosis and treatment across all individuals.

关键词： Psoriatic arthritis   TNF-inhibitors   epidemiology   treatment withdrawal  

摘要： OBJECTIVE:To investigate real-world retention and remission rates in PsA patients initiating a 2 or 3 TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS:Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted cox regression analyses and Chi-squared test, respectively). RESULTS:We included 5233 (2 TNFi) and 1906 (3 TNFi) patients. Twelve-month retention rates for the 2 and 3 TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2 TNFi), and 65%/63% (3 TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2 TNFi), and 58%/65% (3 TNFi).Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2 and 3 TNFi. CONCLUSION:Two-thirds of patients remained on TNFi at 12 months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6 months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

关键词： IL-10   Influenza   MRSA   acute lung injury   pneumonia  

摘要： Immune activation is essential for lung control of viral and bacterial infection, but an overwhelming inflammatory response often leads to the onset of acute respiratory distress syndrome (ARDS). Interleukin-10 (IL-10) plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the current study, we have investigated the role of IL-10 in acute lung injury (ALI) induced by influenza A virus (IAV) and methicillin-resistant (MRSA) coinfection. This unique coinfection model resembles acute pneumonia patients undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor (IL-10R) gene-deficient mice, as well as neutralizing antibodies, here we show that IL-10 deficiency promotes IFN-γ-dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-γ neutralization during coinfection. Further studies using mice with deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-γ/TNF-α hyper-production and acute mortality. Importantly, this anti-inflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and ARDS pathogenesis by counteracting the IFN-γ response.

关键词： IL-10   Smad2   TGF-β1   Th-17   asthma   stigmasterol  

摘要： Stigmasterol is a common dietary phytosterol with high nutritional value and physiological activity. In this study, we evaluated the effects of stigmasterol on inflammatory cytokines and the TGF-β1/Smad2 and IL-17A signaling pathway in an ovalbumin (OVA)-induced asthma mouse model. Stigmasterol treatment improved airway remodeling. In addition, it significantly attenuated the symptoms of asthma attacks, reduced the number of macrophages, lymphocytes, neutrophils, and eosinophils in BALF and inflammatory cytokines, including IL-1β, IL-5, IL-6, and IL-13. It further decreased the level of IL-17A in BALF, serum and spleen. Spleen single-cell suspension analysis via flow cytometry showed that IL-17A level was consistent with the results obtained in BALF, serum and spleen. Stigmasterol decreased the protein expression levels of TGF-β, p-Smad2 and IL-17A in the spleen, by increasing the protein expression level of IL-10. After 24 h of co-culture of TGF-β, IL-6 and stigmasterol, the level of IL-17 in CD4 T cell supernatant was lower relative to levels in the group without stigmasterol. Meanwhile, stigmasterol treatment attenuated the expression level of TGF- β, p-Smad2 and IL-17A proteins in CD4 T cells and enhanced the expression levels of IL-10 protein. These data suggested that stigmasterol inhibited the TGF-β1/Smad2 and IL-17A signaling pathway to achieve anti-asthmatic effects in the OVA-induced asthma mouse model. Collectively, the results of this study are that stigmasterol has achieved preliminary efficacy in the non-clinical laboratory, further studies are needed to consider the clinical application of stigmasterol.