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关键词： Immune system development   Embryonic immunity   Avian   Evolutionary relic   Poultry  

摘要： Chickens are renowned as a model for embryogenesis but have also been responsible for crucial advances in virology, cancer research and immunology. However, chickens are best known as a major source of animal protein for human nutrition, with roughly 80 billion chickens alive each year supplying meat and eggs, the vast majority part of a global poultry industry. As a result, avian immunology been studied intensively for over 60 years, and it has become clear that a major genetic locus in chickens determining resistance to infectious disease and response to vaccines is the major histocompatibility complex (MHC). Compared to typical mammals, the chicken MHC is compact and simple, with only two classical class I genes. A dominantly-expressed class I gene, BF2, is the major ligand for cytotoxic T lymphocytes (CTLs), while the other locus, BF1, is much less wellexpressed, lacking in some MHC haplotypes, and is a ligand for natural killer (NK) cells. Cell surface class I expression in neonatal chicks is far less than in adults, and one possibility is that BF2 is not well-expressed early in ontogeny. A precedent is found for amphibians: the single classical class I molecule is not expressed in tadpoles of Xenopus frogs, although non-polymorphic (and thus non-classical) class I molecules from the XNC locus are expressed, which are recognised for immune defence by non-canonical NKT lymphocytes. Indeed, three waves of different T cells are produced by the Xenopus thymus: in tadpoles, during metamorphosis and finally as adults. Three waves of thymic emigrants are also found for chickens, and reasoning by analogy, it may be that the waves of thymocytes and the expression of class I molecules during ontogeny of chickens are evolutionary relics. As well as scientific interest in the ontogeny of MHC class I expression and appearance of peripheral T cells, there are potential practical implications, given the importance of vaccination in ovo and in day-old chicks for the poultry in

关键词： anti-HLA antibodies   donor selection   engraftment   desensitization strategy  

摘要： Background-Antibodies directed against donor-specific HLA allele(s)/antigen(s) (DSAs) representa known risk factor for hematopoietic stem cell transplantation (HSCT) engraftment. Still, the overall management needs to be standardized. Material and methods-GITMO and AIBT ran a survey on DSAs in Italian Transplant Programs including mismatched HSCT performed between January 2014 and June 2017. Results-One-thousand-thirty-three patients were proposed for the study, 804 were evaluable. Overall, 355 (44%) were screened: 91/355 (25.6%) showed anti-HLA antibodies, 23 DSAs (6.5%). Female gender and at least 4 previous pregnancies showed an impact on alloimmunization. Eleven patients with DSAs underwent desensitization. In seven cases no desensitization was employed. An alternative donor was selected for five patients. Neutrophil and platelet engraftment were obtained in 93.6% and 86.6% of the whole population, respectively, and were statistically associated with the absence of anti-HLA antibodies, ABO match, a higher number of infused nucleated cells and lack of a-GvHD. In addition, significant factors for platelet engraftment were the use of leuco-depleted transfusions, HLA match, younger age of the patient. Graft failure (GF) was associated with bone marrow stem cell source, and a lower number of infused CD34+. The detection of antibodies directed against both HLA classes, donor and patient age, the hematologic and molecular remission at HSCT, HLA match, ANC and PLTS engraftment, full donor engraftment within 28 days after HSCT, early and late GF, grade>II a-GVHD showed an impact on OS. Discussion-Anti-HLA antibodies and DSAs were confirmed as risk factors affecting OS. DSAs were managed with various approaches resulting in stable engraftment in 81.9% of patients. Our study supports the clinical relevance of DSAs detection and management in mmHSCT. A standardized approach of DS is warranted.

关键词： TNF   immunotherapy   CD137L   CD137   monomer   dimer   trimer   MD simulation   binding affinity   structural stability  

摘要： CD137 is a prominent costimulatory molecule of the tumor necrosis factor (TNF) receptor superfamily that activates T cells through a complex bidirectional signaling process involving CD137L. The clinical value of immunotherapies underscores the potential of CD137L/CD137 as an effective target for boosting antitumor immune responses;however, the intricate mechanisms governing these interactions have not been fully elucidated. Herein, we constructed various oligomeric states of CD137L (monomeric, dimeric, and trimeric CD137L) and explored their interactions with CD137 using molecular dynamics simulations. Our findings revealed that trimeric CD137L exhibits higher thermal stability but reduced binding affinity for CD137 compared with the dimer form, with the A'B' loop of CD137L playing a critical role in both structural stability and promoting CD137 interactions. Notably, the formation of hexameric structures enhanced the binding affinity and stability. This study provides valuable insights into the CD137L/CD137 bidirectional signaling mechanisms, which may inform the design of next-generation CD137 agonists. Ultimately, these advancements may improve cancer immunotherapy strategies, aiming to enhance therapeutic outcomes for patients through more effective and targeted therapies.

关键词： cytokines   interleukin-6   luminal A   macrophages   non-responder   T cells  

摘要： Drug non-responsiveness is the major reason for the poor prognosis of hormonal receptor-positive breast cancer (ER+/PR+ BCa), particularly the luminal A subtype. However, the underlying mechanism of drug non-responsiveness remains unknown. Flow cytometry and t-SNE analysis followed by ELISA validation of responder and non-responder unveiled lower secretion of IFN-gamma, IL-12, and higher levels of IL-6 and TGF-beta in CD4(+) T cells (P < 0.001), CD8(+) T cells (P < 0.001), FOXP3(+) Tregs (P < 0.001) and CD206(+) TAMs (P < 0.001) in non-responders. Treatment of isolated CD206(+) TAMs with recombinant IL-6 upregulated the expression of ARG-1 (arginase-1) and subsequent increase of TGF-beta(+) Tregs (P < 0.001) and IL-6(+) Tregs (P < 0.001) in luminal A BCa. Our findings showed IL-6 mediated ARG-1(+)CD206(+) TAMs polarization induced FOXP3(+) Tregs infiltration in TME of non-responder in luminal A BCa.

关键词： ETV6   Fusion   Chronic eosinophilic leukemia   Hypereosinophilia   RNA Sequencing  

摘要： Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm. Diagnosis of CEL is often challenging, notably because of the lack of recurrent and specific molecular event. We report here a case of CEL occurring in a 49-year-old man who presented a persistent hypereosinophilia (HE) associated with anemia and thrombopenia. Karyotyping showed a translocation t(5;12)(q31;p13). Targeted RNA Sequencing identified a novel ETV6::RAPGEF6 fusion gene, confirmed by RT-PCR. Despite several lines of treatment, the patient died after 16 months of duration with transformation to acute myeloid leukemia (AML).Contrary to myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), where fusion genes are both class defining and involve tyrosine kinase genes as the 3' partner, fusion genes are exceedingly rare in non-MLN-TK myeloid malignancies with HE. The most reported fusion gene is ETV6::ACSL6, in rare cases. Previously, overexpression of IL3 (interleukin 3) has been described in myeloid neoplasms with ETV6::ACSL6 (previously named ACS2). In our case of CEL with the ETV6::RAPGEF6 fusion, we also demonstrated overexpression of IL3, which could potentially result from the proximity of the IL3 gene to RAPGEF6, similar to what is observed with ACSL6 and IL3. The use of RNA sequencing in routine diagnosis of CEL could provide evidence for clonal event such as gene fusion, improving diagnosis as well as prognosis and therapeutic approaches.

关键词： Apoptosis   Certolizumab   Neuroinflammation   Spinal cord injury   TNF-alpha  

摘要： ObjectiveSpinal cord injury (SCI), which is characterized by motor and/or sensory dysfunction, presents a significant health challenge resulting from mechanical trauma. Secondary injury, which follows the mechanical trauma and is driven by factors such as inflammation, plays a critical role in the SCI pathophysiology. Scientific evidence indicates that treatment strategies aimed at modulating inflammation during the acute phase of SCI alleviate the seconder injury. In this regard, the present study seeks to evaluate the effectiveness of certolizumab, a monoclonal antibody targeting TNF-alpha that is widely used in the treatment of various inflammatory diseases, in a SCI *** this study, Control, Trauma, and Trauma + Certolizumab groups were established, each comprising eight male rats. One hour after SCI induction, rats in the Trauma + Certolizumab group were administered 10 mu g Certolizumab dissolved in saline intraperitoneally, while rats in the Control and Trauma groups received an equivalent volume of saline. After Modified Tarlov Scoring was performed on the seventh day of the experiment, all rats were sacrificed. The effects of certolizumab on neuroinflammation and apoptosis in the SCI model were evaluated using histological, biochemical, and molecular analyses of blood and tissue samples obtained from the *** downregulated the expression of TNF-alpha, NF-kappa B, and IL-6. In addition, as evidenced by the TUNEL assay, Caspase-3 expression (an apoptotic marker), and Modified Tarlov Score results, certolizumab effectively suppressed inflammation-induced neural apoptosis and alleviated locomotor *** treatment exerts a neuroprotective effect against secondary damage in SCI through the inhibition of neuroinflammation and apoptosis.

关键词： HSCT   GVHD   MTHFR C677T   MTHFR A1298C  

摘要： The impact of non-HLA drug-metabolizing gene polymorphisms on post-transplant outcomes is well recognized. We aimed to evaluate the impact of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1982C and CYP3A4 A290G polymorphisms on the outcomes of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from fully matched siblings. Using PCR-RFLP and according to DNA availability, MTHFR and CYP3A4-V polymorphisms were evaluated. In total 60 patient/donor pairs were investigated. The MTHFR genotypes exhibited similar frequencies in both patients and donors;the MTHFR wild-type in patients correlated with a trend towards reduced incidence of GVHD and improved overall survival rates. Most patients (84.9 %) and donors (76.8 %) had CYP3A4 A wild type. Acute GVHD occurred only in patients with the wild type (10/45 AA vs 0/8 AG or GG) and 9/43 vs 1/13 in recipients from donors with AA vs. AG + GG. GVHD prophylaxis regimens that do not include methotrexate demonstrated a 5.5-fold increased risk of acute GVHD (p = 0.03). Alternative conditioning regimens to Busulphan/Cyclophosphamide exhibited a 19.1-fold increase in the risk of transplant-related mortality (TRM), with statistical significance (p = 0.007). Severe oral mucositis was correlated with male gender (p = 0.03) and a diagnosis of leukaemia (p = 0.007). Renal toxicity is correlated with an age of >= 18 years (p = 0.04) and male gender (p = 0.04). In conclusion, methotrexate in GVHD prophylaxis correlates with a reduced risk of GVHD, while the Busulphan/Cyclophosphamide conditioning regimen is linked to a lower incidence of TRM. Although statistical significance was not achieved due to the predominance of the CYP3A4 wild type, its nearly exclusive association with GVHD may hold clinical significance. Therefore, genotyping patients and adjusting the CsA dose for individuals with the CYP3A4 wild type is recommended.

关键词： TNF-alpha   caspase-3   titanium implants   jawbone fixations   miniplates and screws  

摘要： The aim of the study was to evaluate the effect of titanium implants (Ti6Al4V) on the surrounding tissues by analyzing the concentration of titanium particles, TNF-alpha, and caspase-3 in patients treated for jaw fractures and dentofacial deformities. The research material consisted of peri-implant tissues: fragments of periosteum adhering to a titanium miniplate and blood serum collected from 42 patients treated for mandibular fractures (Group I), and dentofacial deformities (Group II) who underwent bimaxillary osteotomy. The control group consisted of 24 generally healthy patients before bimaxillary osteotomy. The concentrations of selected cytokines, caspase-3, TNF-alpha in blood serum, and homogenized tissues, were determined using the immunoenzymatic method (ELISA). The concentration of titanium particles was assessed using a scanning electron microscope equipped with an X-ray microanalyzer. A significant increase in the concentration of titanium, caspase-3, and TNF-alpha was observed in serum and periosteum in all patients who underwent bone fixation. Increased TNF-alpha levels indicate an intense immune response, which may lead to the degradation of peri-implant tissues and bone resorption around the miniplates and screws, while an increase in caspase-3 levels suggests that cells surrounding the implants are destroyed in response to inflammatory stress or damage induced by the presence of titanium particles.

关键词： CC chemokine receptor 4   interleukin-4   T follicular helper cells   IgG4-related disease   IgG4  

摘要： Objective Human T follicular helper (Tfh) cells are classified into three subsets: Tfh1, Tfh2, and Tfh17 cells. Among them, Tfh2 cells are defined as CXCR3-negative and CCR6-negative, and may contain diverse cell populations. We examined whether CCR4 serves as a marker for identifying Tfh2 cells that produce interleukin (IL)-4 and its involvement in IgG4-related disease (IgG4-RD). Methods Single cell analysis of IL-4-producing Tfh subset was performed using multi-colour flow cytometry and t-SNE method. Blood samples were obtained from 23 treatment-na & iuml;ve patients with active IgG4-RD. CCR4+Tfh2 cells were also assessed in affected tissues of IgG4-RD by flow cytometry and immunohistochemical staining. Results Tfh2 cells expressing CCR4 were identified as Tfh cells that specifically produce IL-4. CCR4+Tfh2 cells showed higher expression of GATA-3 and ICOS than CCR4-Tfh2 cells, while there was no difference in the expression of BCL-6 and FOXP3. The proportion of CCR4+Tfh2 cells in peripheral blood was increased in IgG4-RD compared to healthy controls, and even more CCR4+Tfh2 cells infiltrated into the affected lesions. CCR4+GATA-3+Tfh2 cells diffusely infiltrated tertiary lymphoid tissues and storiform fibrosis lesions. The proportion of CCR4+Tfh2 cells showed a significant correlation specifically with serum IgG4 levels among clinical indicators. Glucocorticoid therapy did not correct the increased proportion of CCR4+Tfh2 cells. Conclusion CCR4 serves as a marker for identifying Tfh2 cells that specifically produce IL-4. CCR4+Tfh2 cells are a widely present T cell population that infiltrates tertiary lymphoid tissues and storiform fibrosis of IgG4-RD. Glucocorticoid fails to effectively target CCR4+Tfh2 cells that may contribute to a high relapse rate during glucocorticoid tapering in this disease.

关键词： abatacept   IFN-gamma   inhibitor of differentiation 2   rheumatoid arthritis   T cell  

摘要： Purpose This research investigates the role of inhibitor of differentiation 2 (Id2) in the synthesis of pro-inflammatory cytokines, specifically interferon-gamma (IFN-gamma) and interleukin-17 (IL-17), by various subsets of T cells, and its pathogenic role in rheumatoid arthritis (RA). Methods Flow cytometry was employed to assess T-cell activation and Id2 expression in 72 RA patients and 23 healthy controls. In vitro, peripheral blood mononuclear cells were treated with either an Id2 inhibitor or a T-cell co-stimulation inhibitor. An in vivo collagen-induced arthritis (CIA) model was established using T-cell-specific Id2 knockout mice. Additionally, follow-up observations were conducted among treated RA patients. Results T-cell activation levels in RA synovial fluid were significantly elevated. A positive correlation was found between increased IFN-gamma and Id2 expression. In vitro, antagonising Id2 reduced IFN-gamma production after T-cell activation. T-cell-specific Id2 knockout mice exhibited a diminished occurrence and severity of CIA, along with a significant decrease in IFN-gamma expression. Clinical monitoring indicated that Id2-induced circulating T-cell IFN-gamma expression significantly decreased following treatment with the T-cell activation inhibitor abatacept. Conclusion The data suggest that high Id2 expression is a critical regulator of pro-inflammatory cytokine upregulation, particularly IFN-gamma, by hyperactivated T cells in RA, potentially exacerbating the disease. Inhibiting Id2 expression or function may offer new therapeutic approaches for RA joint inflammation. Key points Pro-inflammatory cytokines are significantly upregulated in the synovial fluid T cells in rheumatoid arthritis patients. The expression of pro-inflammatory cytokine interferon-gamma (IFN-gamma) positively correlates with the high expression of inhibitor of differentiation 2 (Id2). The inhibition or ablation of Id2 can effectively suppress IFN-gamma production and the onset