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摘要： Le cellule parafollicolari o cellule C della tiroide hanno rappresentato per lungo tempo un mistero per la loro origine embriologica e la loro funzione. Identificate alla fine del XIX secolo, la loro capacità endocrina è stata chiarita, nei Vertebrati, alla metà del 1900 e, poco dopo, ne è stata proposta l’origine dalle creste neurali. Questa prospettiva è rimasta valida sino a pochi anni fa, quando è stato dimostrato, nei Mammiferi e nell’Uomo, che derivano dall’endoderma, ossia dall’intestino primitivo come i tireociti e il loro differenziamento neuroendocrino, assente nei progenitori embrionali, si verifica solo entro il primitivo parenchima follicolare. Pertanto, anche il carcinoma midollare della tiroide, che deriva dalle cellule C, è da considerare una neoplasia epiteliale come l’adenocarcinoma intestinale e non una neoplasia neuroendocrina. La localizzazione delle sue metastasi è, frequentemente, a livello del linfonodo sentinella prelaringeo, o linfonodo di Delfi, confermando l’osservazione ottocentesca che le cellule parafollicolari stabiliscono contatti diretti con i linfatici interfollicolari.

关键词： IL10   anti-inflammatory cytokine   chronic kidney disease   progression  

摘要： BACKGROUND:Anti-inflammatory cytokines is thought to influence the onset and course of chronic kidney disease (CKD). Particular cytokines include Interleukin-10 (IL-10), which is usually considered anti-inflammatory. OBJECTIVES:The current study designed to determine the activity of the IL10 and their roles in chronic kidney disease. METHODS:This research is done, forty- five blood samples were collected from patients with chronic kidney disease and 42 volunteers. A sandwich ELISA was used to estimate the serum levels of human Interleukin-10. RESULTS:The mean age among patient groups (males, females) it was 47.40 ± 2.96 and 62.64 ± 14.46 years, respectively. While the control groups (males, females) were 40.97 ± 1.67 and 45.25 ± 7.13 years (p > 0.05). Of the 45 patients, 20 (44.4%) were males, 25 (55.6%) females. The resulted data showed that there are no significant (p > 0.05) for the total of the mean of human IL-10 between patients and control, respectively, where the mean level of IL10 in males was 190.10 ± 15.07& 154.18 ± 8.77 (p < 0.05) respectively and 142.22 ± 12.43 & 117.04 ± 14.66 in females, but not significantly (p > 0.05), and revealed an highly increased significant in this marker during the course of the chronic kidney disease in males more than females in patients (p < 0.05). CONCLUSION:Can conclude from this study that decreased anti-inflammatory cytokine IL10 likely affects CKD progression and prognosis in females specifically.

关键词： SYT-SSX Fusion Neoantigen   TCR-T Cell Therapy   Stimuli-responsive Nanoparticle   Solid Tumor   Cancer Immunotherapy  

摘要： The adoptive transfer of TCR-T cells specific to neoantigens preferentially exhibits potent cytotoxicity to tumor cells and has shown promising efficacy in various preclinical human cancers. In this study, we first identified a functional TCR, Tcr-1, which selectively recognized the SYT-SSX fusion neoantigen shared by most synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) demonstrated HLA-A*2402-restricted, antigen-specific anti-tumoral efficacy against synovial sarcoma cells, both in vitro and in vivo. Furthermore, to extend its application, we developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into stimuli-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (Neo-AgNPs) for tumor targeting delivery. As expected, Neo-AgNPs were proven to have great tumor penetration and local release. In situ, the modification was able to direct engineered Tcr-T1 against other HLA-A*2402-positive malignant cancer cell lines with significant antigen-specific cytotoxicity despite their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has great potential for further clinical investigation and provides new insight for future TCR-T cell therapy development.

摘要： Gastrointestinal (GI) tract graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remain major goals in this disease. Herein, we identified interleukin-34 (IL-34) as an intestinal epithelium-derived cytokine that was able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that the absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages toward a proinflammatory phenotype and augmented the accumulation of pathogenic CD4+ granulocyte-macrophage colony-stimulating factor (GM-CSF)+ T cells within the colon. Conversely, the administration of recombinant IL-34 substantially reduced GVHD mortality and inflammation, which was dependent on the expression of apolipoprotein E in donor macrophages. Complementary genetic and imaging approaches in mice demonstrated that intestinal epithelial cells were the relevant source of IL-34. These results were supported by colonic biopsies from patients with GVHD, which displayed IL-34 expression in intestinal epithelial cells and apolipoprotein E in lamina propria macrophages, validating similar cellular localization in humans. These studies indicate that IL-34 acts as a tissue-intrinsic cytokine that regulates GVHD severity in the GI tract and could serve as a potential therapeutic target for amelioration of this disease.

关键词： HIV-1   T-cell epitope   HLA-A   antigen-specific T-cell detection   CD8(+) T-cell  

摘要： Background: Although the immune response of host T cells to human immunodeficiency virus (HIV) significantly influences the progression of the infection, the development of T-cell-based vaccines and therapies, as well as the clinical evaluation of specific T-cell functions, is currently markedly hindered by the absence of broad-spectrum, functionally validated HIV T-cell epitopes that account for the polymorphisms of the human leukocyte antigen (HLA) within an indicated geographic population. This study aimed to identify T-cell epitopes derived from the GP160, GAG, and POL proteins of the HIV-1 strain, specifically linked to 12 prevalent HLA-A allotypes, that collectively represent approximately 91% of the total gene frequency in Northeast Asian populations. Methods: A total of 134 epitopes were predicted in silico and selected as potential candidates for further validation. Subsequently, peripheral blood mononuclear cells (PBMCs) were collected from 96 individuals with HIV-1 and cocultured ex vivo with each epitope candidate peptide, followed by the detection of activated CD8(+) T cells. Peripheral blood mononuclear cells (PBMCs) were collected from 96 individuals with HIV-1 and cocultured ex vivo with each candidate peptide epitope, followed by the detection of activated CD8+ T cells. A total of 69 epitopes were validated as real-world HIV T-cell epitopes presented by 12 dominant HLA-A allotypes. Furthermore, the HLA-A cross-restriction for each epitope candidate was identified through peptide competitive binding assays using 12 transfected *** cell lines. Results: A total of 45 epitopes demonstrated high affinity, while 31 epitopes displayed intermediate affinity. A broad-spectrum CD8(+) T-cell epitope library containing 141 validated epitope peptides was used to universally detect HIV-1-specific CD8(+) T cells via peptide-PBMC ex vivo coculture and intracellular IFN-gamma staining. In 52 people with HIV-1, the number of reactive HIV-1 specific CD8(+) T cell

关键词： molecular matching   XGBoost   Snow   PIRCHE   clinical prediction model   kidney transplantation   epitope matching  

摘要： Introduction The immune-mediated rejection of transplanted organs is a complex interplay between T cells and B cells, where the recognition of HLA-derived epitopes plays a crucial role. Several algorithms of molecular compatibility have been suggested, each focusing on a specific aspect of epitope *** Considering reported death-censored graft survival in the SRTR dataset, we evaluated four models of molecular compatibility: antibody-verified Eplets, Snow, PIRCHE-II and amino acid matching. We have statistically evaluated their co-dependency and synergistic effects between models systematically on 400,935 kidney transplantations using Cox proportional hazards and XGBoost *** Multivariable models of histocompatibility generally outperformed univariable predictors, with a combined model of HLA-A, -B, -DR matching, Snow and PIRCHE-II yielding highest AUC in XGBoost and lowest BIC in Cox models. Augmentation of a clinical prediction model of pre-transplant parameters by molecular compatibility metrics improved model performance particularly considering long-term *** Our study demonstrates that the use of multiple specialized molecular HLA matching predictors improves prediction performance, thereby improving risk classification and supporting informed decision-making in kidney transplantation.

关键词： TGF-beta-receptor   TGF-beta-signaling   SMADs   Mast cell differentiation   MCPT1   IL-3   ERK1/2  

摘要： Mast cells develop from the myeloid lineage and are released from the bone marrow as immature cells, which then differentiate at the destination tissue based on cues from the local environment. In the liver, mast cells are recruited in diseased states to fibrogenic surroundings rich in TGF-beta 1. The aim of this study was to investigate TGF-beta 1 signaling in primary and permanent mast cells to identify common and unique mechanisms. The TGF-beta receptor repertoire is similar among mast cells, with high expression of type I and type II receptors and very low expression of type III receptors (Betaglycan and Endoglin). Downstream, TGF-beta 1 activates the SMAD2/3 signaling axis and also SMAD1/5 with target genes Smad6 and Id1 in a transient manner. Initially, TGF-beta 1 upregulates the transcription of mucosal mast cell effectors Mcpt1 and Mcpt2 in all analyzed mast cells. This upregulation is reduced in the presence of IL-3, which promotes proliferation. Inhibition of ERK1/2 activation reduces proliferation and mitigates the negative effect of IL-3 on Mcpt1 mRNA and protein expression in the immortalized mast cell line PMC-306 but not in bone marrow-derived mast cells. Therefore, extracellular signal-regulated kinases ERK1/2 are identified as a mutual switch between IL-3-driven proliferation and TGF-beta 1-promoted mucosal mast cell differentiation in PMC-306. In conclusion, TGF-beta 1 promotes a mucosal gene signature and inhibits proliferation in mast cells, with these effects being counter-regulated by IL-3/ERK1/2.

关键词： 原发性肝细胞癌   单核苷酸多态性   人类白细胞抗原   临床病理特征   预后  

摘要： 目的　分析人类白细胞抗原(HLA)基因单核苷酸多态性(SNPs)与原发性肝癌(HCC)临床病理特征和术后预后之间的关联性。方法　选取2014年1月－2022年9月在青岛大学医学院附属烟台毓璜顶医院接受手术治疗且住院资料完整的328例原发性HCC患者进行回顾性分析。采用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)检测所有患者HLA-DRB1 rs2647073、rs3997872及HLA-DQB1 rs1049055位点的基因型。采用二元logistic回归分析HLA基因SNPs与原发性HCC临床病理特征之间的关系，并以年龄、性别、饮酒史和HBV/HCV感染史作为分层因素进行分层分析。采用单因素Cox回归分析HLA基因SNPs与术后预后的相关性并绘制原发性HCC患者术后的Kaplan-Meier生存曲线，采用多因素Cox回归分析影响原发性HCC患者术后预后的独立危险因素。结果　二元logistic回归分析结果显示，rs2647073位点CC基因型患者肿瘤直径≥5 cm的风险较AA基因型患者高(P=0.005)；rs3997872位点TT基因型患者发生脉管侵犯的风险较AA基因型患者高(P=0.003)。分层分析显示，在年龄≥60岁、有HBV/HCV感染史、女性、男性、无饮酒史和有饮酒史的患者中，HLA-DRB1 rs2647073位点CC基因型者肿瘤直径≥5 cm的风险均高于AA+AC基因型者(P<0.05)。在年龄≥60岁的患者中，HLA-DRB1 rs3997872位点TT基因型者发生脉管侵犯的风险高于AA+AT基因型者(P=0.000)。而无论在男性、女性，有饮酒史、无饮酒史，有HBV/HCV感染史、无HBV/HCV感染史的患者中，HLA-DRB1 rs3997872位点TT基因型者发生脉管侵犯的风险均高于AA+AT基因型者(P<0.05)。多因素Cox回归分析显示，HLA-DRB1 rs3997872位点TT基因型患者较AT+AA基因型患者术后预后差(校正HR=1.384，95%CI 1.056～1.814，P=0.019)。HLA-DRB1 rs3997872位点SNP(校正HR=1.384，95%CI 1.056～1.814，P=0.019)、年龄增大(校正HR=1.032，95%CI 1.018～1.047，P=0.000)、HBV/HCV感染史(校正HR=2.056，95%CI 1.490～2.836，P=0.000)、包膜侵犯(校正HR=1.651，95%CI 1.166～2.337，P=0.005)、脉管侵犯(校正HR=1.498，95%CI 1.072～2.603，P=0.018)、BCLC分期较晚(校正HR=5.774，95%CI 2.777～12.003，P=0.000)、非根治性手术方式(校正HR=0.552，95%CI 0.330～0.924，P=0.024)、体力活动状态(PS)评分增高(校正HR=1.784，95%CI 1.081～2.944，P=0.023)是HCC患者术后预后的独立危险因素。结论　HLA-DRB1 rs2647073、rs3997872位点SNPs与原发性HCC的临床病理特征相关，rs3997872位点SNP与HCC患者的术后预后相关。

摘要： Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes sudden cardiac death and progressive heart failure. Besides fibro-fatty replacement and myocyte degenerative changes, inflammatory patchy infiltrates are found in myocardial histological analysis of ACM patients. Inflammatory cells could actively participate in ACM pathogenesis, contributing to the alteration of cardiac microenvironment homeostasis, thus triggering disease evolution. In order to characterize the immune-derived mediators involved in ACM pathogenesis, peripheral blood mononuclear cells from ACM patients were characterized and compared to healthy controls' ones. Flow cytometry analysis revealed a lower frequency of CD4+ T helper type 1 cells, NK cells, and terminally differentiated CD8+ EMRA+ T cells in ACM patients compared to age-matched controls. In contrast, a higher proportion of effector/memory FOXP3+ CCR4+ CD45RO+ regulatory CD4+ T cells (Treg) were found in ACM patients. Single-cell RNA-seq performed on isolated memory Treg cells (mTreg) from ACM patients and healthy controls identified 6 clusters characterized by specific gene signatures related to tissue repair and immunosuppressive pathways. Notably, interleukin 32 (IL-32) was the most differentially expressed gene in ACM patients mTreg with respect to healthy controls. Treatment of human cardiac mesenchymal stromal cells with recombinant IL-32 in vitro promoted lipid droplet accumulation and collagen deposition, thus identifying IL-32 as a new potential player in the immune-mediated trigger of cardiac fibro-fatty replacement in ACM. Overall, we here provide the first complete characterization of circulating ACM immune cells, revealing an abundance of Treg. The high expression of IL-32 in ACM Treg may contribute to accelerated cardiac remodeling in ACM patients' hearts.

关键词： transplantation   CD4+ T cells   indirect allorecognition   epitope   TCR   tolerance   HLA   co-stimulation   pruning   antigen discovery  

摘要： Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSAs) posing the highest rejection risk. Here, we investigated the role of indirect CD4+ T cell epitopes-donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II-in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides. Antigen mapping of indirect CD4+ T cell epitopes in a mouse model of fully MHC mismatched skin graft transplantation (BALB/c to C57BL/6) identified a similar epitope (amino acids 287-301) derived from the donor H2-Kd. Tetramer-binding Kd287+ CD4+ T cells were detected during rejection and their transfer into T cell-deficient mice induced DSA. Systemic delivery of high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287+ CD4+ T cells and DSA formation. Thus, targeting a narrow range of donor antigens may prevent DSA formation and improve transplant outcomes.