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关键词： ILC3   RORγt   IL-22   HB-EGF   gut homeostasis  

摘要： ROR gamma t inhibition shows potential for treating T helper 17 (Th17) cell-related inflammatory disorders. However, there is a lack of a comprehensive understanding of its influence on the immune system. ROR gamma t also serves as the master regulator of type 3 innate lymphoid cells (ILC3s). Although previous studies indicated that it might not be essential for ILC3 activation, our single-cell RNA sequencing analysis reveals its fundamental participation. By utilizing an Il22Cre/+Rosa26LSL-TdtomatoRorcfl/fl (interleukin [IL]-22-fate mapping [FM]Delta Rorc) mouse model, we discovered that genetic deletion of Rorc does not completely eliminate ILC3s. Only the lymphoid tissue inducer (LTi) subset experiences a reduction. Additionally, the "ex-ILC3s" following Rorc deletion still preserve ILC3 characteristics and produce sufficient IL-22 to maintain gut health and prevent pathogen invasion. Nevertheless, ROR gamma t is found to be crucial for heparin-binding epidermal growth factor (HB-EGF) production in activated ILC3s, which is of great significance in alleviating colitis. Thus, our findings clarify the role of ROR gamma t in ILC3s, thereby providing insights for the clinical evaluation of ROR gamma t inhibition.

关键词： immunotherapy   HLA-peptide binding   protein language model  

摘要： Predicting the binding of peptides to human leukocyte antigen (HLA) alleles is critical for identifying epitopes initiating immune responses in vaccine development and immunotherapies. Despite the progress in predicting binding peptides of 1% HLA class-I alleles with in silico prediction tools, it remains challenging to predict binding peptides for alleles lacking epitopes. To achieve the binding prediction on those zero-shot alleles, we developed a hierarchical progressive learning (HPL) framework that progressively learns sequence patterns of specific peptide-HLA complexes. HPL models improve the prediction performance for zero-shot HLA class-I alleles by 60.8% (1,414.0% for non-classical ones). We further developed an automated peptide mutation search program, which automatically identifies binding peptides for any target HLA class-I allele and mutates weak-binding or non-binding peptides to enhance binding affinity under the guidance of HPL models. Our program generated high-affinity binding candidates of any target allele with limited mutations in more than 38.1% of testing cases.

关键词： IL-36   Aspergillus   invasive pulmonary aspergillosis   stem cell transplantation   single-nucleotide polymorphism  

摘要： Background Genetic predisposition plays a major role in the development of invasive pulmonary aspergillosis (IPA). The risk and course of IPA vary significantly among patients, yet continuously new genetic mechanisms that influence individual antifungal immune responses are being discovered. While genetic variability in interleukin (IL)-1 family cytokines is recognized as an important cause of disease susceptibility, it is unclear whether and how less-studied IL-1 family members, such as the IL-36 cytokine subfamily, are genetically regulated and influence the risk of *** We analyzed how genetic variants in the IL36 loci associate with the risk of IPA in 328 eligible recipients of allogeneic hematopoietic stem cell transplants and their corresponding donors. The functional consequences of relevant genetic variants were investigated using clinical samples and in vitro infection *** We report that recipient, but not donor, single-nucleotide polymorphisms (SNPs) rs895497 in IL36A and rs4849142 in IL36B increase the risk of IPA after transplantation. The strongest contribution of these SNPs to infection risk was observed in a combined analysis of transplant pairs. IL-36 beta was expressed in both human type II-like alveolar epithelial cells and macrophages following Aspergillus fumigatus infection. The risk genotype was associated with impaired production of IL-1 beta in bronchoalveolar lavage fluid samples from infected patients, as well as in fungal-stimulated macrophages. Moreover, macrophages harboring the risk genotype exhibited impaired fungicidal *** Our findings suggest that genotype-specific mechanisms mediated by IL-36 beta act on the nonhematopoietic compartment, can impair antifungal immune responses in macrophages, and ultimately predispose to transplant recipient susceptibility to IPA. We identified an association between genetic variation in IL-36 beta and the risk of invasive pulmonary aspergillosis in allogeneic

关键词： 类受体蛋白激酶   AtORPK1   拟南芥   原核表达   多克隆抗体  

摘要： 富含亮氨酸重复序列的受体样激酶(leucine-rich repeat receptor-like kinase,LRR-RLK)是一类富含亮氨酸的单跨膜类受体蛋白激酶,也是植物类受体蛋白激酶家族中最大的亚家族。本研究通过分段克隆LRR-RLK家族的氧化应激相关蛋白基因(oxidative-stress related protein kinase 1,AtORPK1)编码序列构建原核表达载体,转化至大肠杆菌BL21,经IPTG诱导获得重组蛋白,并纯化出可溶性的AtORPK1蛋白C端。经免疫兔子获得了多克隆抗体,通过免疫荧光和western blot实验验证多克隆抗体与目的蛋白识别的特异性。本研究成功利用大肠杆菌表达了AtORPK1蛋白C端,并获得特异性良好的多克隆抗体,为快速制备植物富含亮氨酸单跨膜类受体蛋白的抗体提供了有效方法;获得的多克隆抗体可用于检测并鉴定目的蛋白在植物中的表达水平,还可用于免疫荧光分析,快速定位目的蛋白在植物细胞和组织中的分布,为研究植物类受体蛋白激酶信号通路的分子机理奠定基础,也为黄河流域盐碱地抗逆植物的分子育种提供参考依据。

关键词： sequential lymphomas   DLBCL   cHL   HLA system   autoimmunity  

摘要： The sequential occurrence of diffuse large B-cell lymphoma (DLBCL) in a patient diagnosed with classical Hodgkin lymphoma (cHL) or vice versa represents a rare situation. In parallel, human leukocyte antigen (HLA) has been studied extensively about rising susceptibility in various lymphomas. Herein, we present clinical characteristics, the outcome and the results of HLA class-I and class-II investigation in patients sequentially diagnosed with the above-mentioned combination of lymphomas. We describe 8 patients (6 males/2 females) with median age at diagnosis of first and second lymphomas of 45.5 years (range: 25-74 years) and 57.5 years (range: 30-83 years), respectively. The median interval between the first and the second diagnosis was 6.5 years (range: 4-22 years). Regarding HLA investigation, we observed that four of our patients were HLA-DQB1*03:01 positive. Interestingly, three of our patients displaying this HLA allele developed a third lymphoma. Notably, we observed that the HLA profile of three other patients revealed the presence of HLA-B*35:03. Interestingly, both above-mentioned HLA alleles have been associated with autoimmune manifestations. Although the presence of certain HLA alleles in our patients could be coincidental, our results suggest that HLA typing may be a field of investigational interest regarding patients with sequential lymphomas.

关键词： IL-33   Treg   skin   immune-surveillance   cancer   inflammation   cSCC   type 2 immunity   ST2 receptor  

摘要： Interleukin (IL)-33 is constitutively expressed in many epithelial tissues at steady state and signals through the receptor, ST2. IL-33 is released upon tissue injury and functions as an endogenous danger signal to alert the immune system to tissue damage. Here we investigate the physiological role of the IL-33/ST2 axis in skin homeostasis and cancer development. We show that the expression of IL-33 differentiates malignant from normal and benign human tissues and that in mouse models of cutaneous squamous cell carcinoma the IL-33/ST2 axis protects against carcinogenesis. Tissue regulatory T cells (Tregs) are the predominant cells expressing ST2 in the skin and localize around the hairfollicle and IL-33 + epithelial cells (ECs). Adoptive transfer experiments demonstrate that skin Tregs regulate EC differentiation, minimizing mutational load and restraining cancer development after exposure to an environmental carcinogen. Our findings indicate an important role for EC-Treg cross-talk as an early checkpoint for containing tissue damage and carcinogenesis.

关键词： fibroblast-like synoviocytes   IL-6R   inflammation   rheumatoid arthritis   YTHDF2  

摘要： This study examined YTHDF2's role in modulating IL-6R signaling to regulate synovial fibroblast inflammation and bone damage in rheumatoid arthritis (RA). Synovial tissues of RA patients were collected. Human fibroblast-like synoviocyte (FLS), MH7A cell line, was induced with TNF-alpha and transfected. Cell proliferation was assessed using MTT and EdU assays;apoptosis was measured with flow cytometry, and migration and invasion were evaluated through scratch and Transwell assays. Lentiviral vectors designed to overexpress YTHDF2 or IL-6R were created to study their effects in mice with collagen-induced arthritis (CIA). Pathological changes of ankle joints in mice were observed, and TNF-alpha, IL-1 beta, and IL-6 contents were determined. MMP3 and MMP9 levels were detected by Western blot, while YTHDF2 and IL-6R were detected by RT-qPCR and Western blot. The binding relationship between YTHDF2 and IL-6R was studied. YTHDF2 in synovial tissues of RA patients was down-regulated. Elevating YTHDF2 inhibited TNF-alpha-induced MH7A cell proliferation, migration, invasion, and pro-inflammatory factors;Knocking down YTHDF2 showed the opposite effect. Upregulating YTHDF2 improved synovial inflammation and bone damage in CIA mice. IL-6R in synovial tissues of patients was significantly up-regulated and negatively correlated with YTHDF2 expression. YTHDF2 reduced IL-6R mRNA stability in a m6A-dependent manner. Overexpressing IL-6R impaired the anti-proliferating and anti-inflammatory effect of YTHDF2 on TNF-alpha-induced MH7A cells. In CIA mice, overexpression of IL-6R reversed the benefits on synovial inflammation and bone injury mediated by up-regulating YTHDF2. YTHDF2 inhibits inflammation and bone damage in RA synovial fibroblasts by reducing the mRNA stability of IL-6R.