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关键词： luminex testing   HLA antibodies   non-HLA antibodies   AT1RAbs   assay standardization  

摘要： Evidence for the contribution of non-HLA antibodies on long-term allograft outcome was suggested in early studies by Paul Terasaki and colleagues who showed worse 10-year allograft outcome in HLA identical kidney transplant recipients with a positive panel reactive antibody (PRA) as determined by the micro cytotoxicity assay, in which cells express other targets beside HLA. More recent reports have shown worse graft outcome when antibodies against non-HLA antigens were detected with HLA-donor specific antibodies (HLA-DSA), and even suggest that non-HLA antibodies may serve as precursor to development of HLA antibodies. Unfortunately, the recent studies lack reproducibility, which then leads to skepticism as to the relevance of non-HLA antibody in transplantation outcome. Consequently, routine testing for non-HLA antibody along with monitoring of HLA-DSA as part of a post-transplant immune surveillance protocol is not standard practice. The Sensitization in Transplantation: Assessment of Risk (STAR) workgroup summarized the current literature on this topic, citing differences in cohort characteristics, variability in study design, selection of sample and timepoints for testing and variability in the assays used to detect non-HLA antibodies, as reasons that impact the accurate assessment on the relevance of non-HLA antibodies. However, correlation between test results and outcome can only be determined if the assay in question is detecting the correct analyte. Therefore, here we will make the case for a plan that requires a systematic validation of high-throughput bead-based assays, to include appropriate sequence selection for non-HLA antigenic targets and quality control metrics as a first step to solving this puzzle.

关键词： Paraquat   IL-17A   Microglial phagocytosis   CD36   Amyloid-(3   alpha-Synuclein  

摘要： Paraquat (PQ), an environmental neurotoxin, has been demonstrated to induce pathological protein aggregation and thus neurotoxicity. Nevertheless, the exact mechanisms remain elusive. In this investigation, we explored the involvement of interleukin-17A (IL-17 A) in the aggregation of amyloid-(3 (A(3) and alpha-synuclein (alpha-syn) induced by PQ. Combining in vitro and in vivo, we explored whether PQ leads to A(3 and alpha-syn aggregation through IL-17 A-mediated reduction in microglia phagocytosis, thereby aggravating neurotoxicity. The results demonstrated that low-dose PQ continuous exposure significantly elevated IL-17 A levels in the peripheral blood serum and prefrontal cortical regions of mice. It also suppressed microglial phagocytosis of pathological proteins and promoted the aggregation of A(3 and alpha-syn in the prefrontal cortex. These changes ultimately resulted in depression, anxiety, and cognitive impairments. Mechanistically, IL-17 A inhibited the expression of the microglial phagocytic receptor CD36, impairing the microglial ability to clear A(3 and alpha-syn. Furthermore, administering an anti-IL-17 A effectively restored microglial phagocytosis in PQ-exposed mice, reduced A(3 and alpha-syn aggregation in prefrontal cortical areas, and alleviated behavioral deficits. In conclusion, this paper highlights IL-17 A as a pivotal mediator in PQ-induced neurotoxicity. It provides a potential target for developing novel therapeutic strategies against neurodegenerative pathologies induced by such environmental toxicants.

关键词： soluble MHC class I chain-related protein A   sMICA   biomarker   graft-versus host disease   GvHD   allogeneic hematopoetic stem cell transplantation  

摘要： Introduction MHC class I chain-related protein A (MICA) acts as a marker of cellular stress and its expression is a destruction-signal for NKG2D-expressing cytotoxic cells. Soluble MICA (sMICA) concentrations after allogeneic hematopoietic stem cell transplantation (HSCT) were associated with worse outcomes and graft-versus-host disease (GVHD). We hypothesized that (i) sMICA could be a prognostic biomarker for the development of GVHD and (ii) may act as an acute phase reactant. Methods In this prospective study we included 48 patients undergoing HSCT and drew blood samples before conditioning (baseline), during engraftment and 100 days after HSCT. The follow-up period was 1 year for each patient. Soluble MICA and established acute phase reactants (C-reactive Protein, von Willebrand Factor) were measured by enzyme-linked immunoassay (ELISA). Results Of the 44 patients in the final analysis, 30 (68%) developed GVHD (16 acute GVHD, 8 chronic GVHD, 6 acute and chronic GVHD). Soluble MICA concentrations at baseline and during engraftment were significantly higher in patients who developed acute or chronic GVHD (p = 0.017). Receiver operating characteristic (ROC) curve analysis for the baseline values showed an area under the curve of 0.78 (p < 0.001;95% confidence intervals 0.64-0.91) for diagnosis of acute or chronic GVHD. Soluble MICA concentrations above 93.5 pg/mL had a specificity of 93% for the diagnosis of GVHD, while the sensitivity was only 47%. Discussion Soluble MICA did not correlate with other acute phase reactants and remained stable during engraftment. Soluble MICA may potentially serve as a biomarker with high specificity for the prediction of GVHD.

关键词： angiogenesis   early gastric cancer   endothelial cells   italic>IL-33   tumor microenvironment   organoids   single-cell RNA sequencing  

摘要： Early gastric cancer (EGC) represents a critical stage in preventing and controlling the progression from gastritis to advanced gastric cancer (AGC). Therefore, identifying the single-cell characteristics of EGC, particularly the cellular composition of the tumor microenvironment (TME), as well as identifying potential predictive markers and therapeutic targets, could significantly enhance the monitoring of gastric cancer and improve clinical cure rates. We constructed a comprehensive single-cell RNA sequencing atlas for 184,426 high-quality gastric cancer cells from various stages, utilizing clinical biopsies and surgical samples. Our single-cell atlas highlights the cellular and molecular characteristics of EGC. Eight distinct cell lineage states were identified, and it was observed that the number of epithelial cell meta-clusters gradually decreased, while the number of T&NK, B, plasma, fibroblast, myeloid, and endothelial cells increased with disease progression. Certain epithelial subclusters (metaplastic stem-like cells (MSCs), pit mucous-like cells (PMC-like), proliferating cells), T-cell subclusters (Treg, CCR7+ naive, CH25H+ CD4+, TEM CD8+, and GFPT2+ CD8+ T cells), and endothelial subclusters (IL-33+ Venous-1 and AMAMTSL2+ Artery-2) were found to be increased in EGC. The Venous-1 subcluster was found to express high levels of IL-33. Mechanistically, it was revealed that IL-33 enhances the survival and angiogenesis of endothelial cells by upregulating the expression of adhesion proteins CD34 and PECAM1. Patient-derived EGC and AGC organoids were subsequently generated, and it was demonstrated that endothelial-derived IL-33 promoted the growth of both EGC and AGC organoids ex vitro and in vivo. Furthermore, IL-33 was found to increase the expression of KRT17 in EGC organoids. Notably, we also found that high expression of IL-33 was positively correlated with the depth of invasion and malignancy of EGC. This study provides novel insights into the single-cell

摘要： In this issue of Blood, Garcia-Lacarte et al identify autocrine and paracrine activities of lymphoma cell-derived interleukin-10 (IL-10) in a murine diffuse large B-cell lymphoma (DLBCL) model that may be exploited for tailoring immunotherapy interventions.(1)

关键词： Yellow fever virus   A549 cells   Mitochondrial network dynamics   Mitophagy   IFN-I   TLR2  

摘要： It has been emphasized that mitochondria play a fundamental role not only in cellular bioenergetics but also in the defense against infections. Here, we investigated mitochondrial network dynamics (MND) and IFN-I(3 signaling response in epithelial A549 cells after yellow fever virus (YFV) infection. We analyze the MND when only some cells are infected at 1 day post-infection (dpi) and after the spread of viral infection, at 3 dpi. Confocal microscopy and MiNA analysis showed that YFV infection leads to a decrease in the number of branches at 3 dpi and an increase in the length of branches at 1 and 3 dpi, suggesting that mitochondrial fission and fusion occur. Consistent with both processes, we found increased transcription of mitofusin 1 and Drp1 and increased colocalization of mitochondria with Drp1 at 3 dpi. In addition, mitochondrial membrane polarization decreased, mtROS production increased, p62 expression decreased, and LC3 expression increased, suggesting an increase in mitophagy flux. We found decreased expression of the IFN inducers RIG-I and MAVS sensors in YFV-infected A549 cells a t 3 dpi. Surprisingly, increased IFN-I(3 levels were observed at transcriptional and protein levels along with IRF7 induction at 1 and 3 dpi. Using the blocking antibody against TLR2, we showed that IFN-I(3 and IL-6 synthesis is maintained by TLR2 signaling. Mechanistically, infection led to activation of the NFxB pathway by degradation of IkBa, and increased phosphorylation of P65 and ERK MAPK signaling. Our results show that YFV infection induces altered MND in epithelial cells and triggers TLR2 signaling.

关键词： tumor necrosis factor alpha   interleukin 6   rheumatoid arthritis   depression  

摘要： Background/Aim: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, characterized by the production of numerous pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta), which lead to pathophysiological changes in innate and acquired immunity. The existing evidence shows that pro-inflammatory cytokines in rheumatoid arthritis impact monoaminergic neurotransmission, neurotropic factors, and synaptic activity, which may lead to the development of depression. Materials and Methods: In our study, we explored the association between TNF-alpha and IL-6, disease activity, and the degree of depression in patients with RA. The association between TNF-alpha and IL-6 and the Beck and Hamilton depression scales was analyzed in a group of 116 RA patients with depression. We investigated the same correlation in 45 patients with primary depression who represented the control group. Results: A Spearman test showed that IL-6 levels had a positive association with the Beck and Hamilton scales (p < 0.05) and that TNF-alpha had a positive association with the Hamilton scale (p < 0.05). Also, the Hamilton depression scale was the more sensitive scale in the detection of depressive symptoms. Conclusions: Our study indicates that elevated values of pro-inflammatory cytokines are associated with the degree of depression in patients with RA. Future preclinical and clinical studies will contribute to a better understanding of the pathophysiological mechanism of depression in patients with RA and may serve as the basis for new treatment modalities. By detecting depression promptly, with the help of the HAM-D as the more sensitive scale, we could influence the future modality of treatment, and with a multidisciplinary approach, we could ensure an improvement in the quality of life of patients with RA.

关键词： IL-17   IL-33   eosinophil   neutrophil  

关键词： vascularized composite allotransplantation   gamma delta T cell   classical monocyte   IL-17   mouse   IFN-gamma   perforin   granzyme  

摘要： Background Vascularized Composite Allotransplantation (VCA) is an important therapeutic option for patients that incur debilitating injuries to the face or limbs. The complexity and immunogenicity of tissue types within VCA grafts pose unique challenges and necessitate the use of intensive immunosuppression;however, graft rejection remains a challenge in VCA. Methods Deep proteomic profiling and high dimensional analysis with cytometry time of flight were used to define the cell types and effector mechanisms elicited by VCA in BALB/c (H-2Kd) > C57BL/6 (H-2Kb) limb recipients. Spleen and cervical draining lymph nodes were collected post-transplant days 1, 3, 5, and 7 (n =4-6 mice/group/day). We identified dynamic, coordinated signatures in T cell and monocyte populations associated with VCA allograft rejection. ResultsIn comparison to syngeneic transplant recipients, allogeneic recipients exhibited significant alterations in the immune cell populations within secondary lymphoid tissues. These changes included very early expansion of double-negative TCR beta(-) T cells, including IL-17A-producing gamma delta T cells, and patrolling monocytes. Subsequently, CD8+CD62L+ T cells and CD8+ effector/effector memory T cells (Teff/Tem), Ly6C(hi)CCR2(hi)CX3CR1(low) classical monocytes, CD4+ Teff/Tem, and CD8+CD25(hi)CCR7(low) Teff/Tem were increased by day 5. CD8+CD25(hi)CCR7(low) Teff/Tem with the highest expression of IFN-gamma, perforin, and granzyme B were enriched by day 7. Conclusions High dimensional proteomic analysis reveals multiple innate and Teff/Tem subsets in acute rejection following VCA. In particular, IL-17A-producing gamma delta T cells and classical monocytes may be particularly important in initiating the alloimmune response in VCA recipients.