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关键词： DERMATOPHYTOSES   ILC3   MYCOSES   T CELLS  

摘要： Fungal skin infections significantly contribute to the global human disease burden, yet our understanding of cutaneous immunity against dermatophytes remains limited. Previously, we developed a model of epicutaneous infection with Microsporum canis in C57BL/6 mice, which highlighted the critical role of IL-17RA signaling in anti-dermatophyte defenses. Here, we expanded our investigation to the human pathogen Nannizzia gypsea and demonstrated that skin γδTCRint and CD8/CD4 double-negative βTCR+ T cells are the principal producers of IL-17A during dermatophytosis. These IL-17A+ T cells exhibited an activated/memory phenotype, including a subset of proliferating tissue-resident cells. Notably, restriction of lymphocyte trafficking following fingolimod administration in infected mice did not lead to increased susceptibility indicating that local antifungal defenses are independent of T cell priming in lymph nodes. Additionally, Rag1-/- mice lacking T and B lymphocytes effectively controlled infection and exhibited increased IL-17A production by innate lymphoid cells (ILCs). Furthermore, Rag2-/-Il2rg-/- mice, devoid of T, B, and ILCs cells, were highly susceptible to dermatophytosis compared to Rag2-/- or WT mice, demonstrating that ILCs are sufficient to antifungal defenses in T cell-deficient mice. In conclusion, our study underscores the coordinated interplay between skin γδT, αβT, and ILCs subsets in controlling primary N. gypsea dermatophytosis.

摘要： OBJECTIVE:Genetic associations and blockade of the interleukin-23/IL-17 axis with monoclonal antibodies support a role for this pathway in psoriatic arthritis (PsA). This study examines the requirement of IL-23 for IL-17 production, and the role of the metabolic microenvironment in the expansion of Th-derived cells in PsA. METHODS:PsA patient synovial fluid or peripheral blood Th cell frequencies were evaluated by flow cytometry using CCR6, CD161 and T-bet as phenotypic markers, and the cytokines IFN-γ, GM-CSF and IL-17 assessed by flow cytometry and ELISA. The impact of IL-23 and metabolic stress on T cell differentiation was investigated. RESULTS:Polyfunctional IL-17 CD4 (p<0.0001) & CD8 (p<0.0001), and GM-CSF Th-derived (p<0.0001) cells were increased in inflamed joints of patients with PsA, with a proportional decrease in patient peripheral blood. We demonstrate IL-23-independent IL-17 release by PsA patient CD4 T cells, where the absence of IL-23 during Th differentiation reduced IL-17 by 31±5.8%. Exogenous IL-23 increased IL-17, negatively regulated GM-CSF and co-operated with TGF-β to augment IL-17. Polyfunctional Th and Th-derived cells, but not Th cells, were expanded by metabolic stress in patients with PsA. CONCLUSIONS:We confirmed the abundance of polyfunctional Type CD4 and CD8 cells in PsA inflamed joints. We demonstrate IL-23-independent expansion of Th cells, where IL-23 negatively regulates GM-CSF. This may account for therapeutic differences in IL-17 and IL-23 inhibition in PsA and the Spondyloarthritides. Polyfunctional IL-17 Th, and Th-derived but not Th cells, were expanded by metabolic stress, where metabolic stress may itself represent a unique therapeutic target.

关键词： Anakinra   IL-1 beta   inflammation   noise-induced hearing loss   treatment  

摘要： ObjectiveThis study aimed to attenuate cochlear inflammation following noise-induced hearing loss by targeting IL-1. We evaluated the effectiveness of IL-1 inhibition through auditory and histological assessments in an animal model. Study designExperimental animal study. SettingGazi University Faculty of Medicine, Ankara, Turkey. MethodsTwenty-four rats were randomly assigned into 3 groups: Anakinra, dexamethasone, and control groups. All animals were exposed to broadband noise (110 dB SPL, 8 hours), auditory brainstem response (ABR) tests were conducted before noise exposure, immediately after, and on Day 14. Anakinra, dexamethasone, and saline were administered intraperitoneally, cochlear tissues were harvested for histological and immunohistochemical evaluation. ResultsOn Day 14, ABR thresholds in Anakinra group were better than the control group across all frequencies, with a significant difference observed at 8 kHz (P = .036). The mean number of OHC was significantly higher in Anakinra group compared to the control group (P < .05). The mean number of IHC in the Anakinra group was greater than in the dexamethasone group. IL-1 beta immunopositivity in the stria vascularis and spiral ganglia was significantly higher in Anakinra group compared to dexamethasone group (P = .022 and P = .013, respectively). TNF-alpha immunopositivity in the stria vascularis and spiral ganglia was significantly greater in control group than in Anakinra group (P = .037 and P = .01, respectively). ConclusionThe comparable efficacy of Anakinra and dexamethasone in both histological and auditory assessments suggests that Anakinra may serve as a promising therapeutic option for noise-induced hearing loss.

摘要： Pluripotent stem cells provide opportunities for treating injuries and previously incurable diseases. A major concern is the immunogenicity of stem cells and their progeny. Here, we have dissected the molecular mechanisms that allow natural killer (NK) cells to respond to human pluripotent stem cells, investigating a wide selection of activating and inhibitory NK cell receptors and their ligands. Reporter cells expressing the activating receptor NKG2D responded strongly to embryonic stem (ES) cell lines and induced pluripotent stem (iPS) cell lines, whereas reporter cells expressing the activating receptors NKp30, NKp46, KIR2DS1, KIR2DS2 and KIR2DS4 did not respond. Human ES and iPS cells invariably expressed several ligands for NKG2D. Expression of HLA-C and HLA-E was lacking or low, insufficient to trigger reporter cells expressing the inhibitory receptors KIR2DL1, -2DL2 or -2DL3. Similar results were obtained for the pluripotent embryonic carcinoma cell lines NTERA-2 and 2102Ep, and also iPS cell-derived neural progenitor cells. Importantly, neural progenitor cells and iPS cell-derived motoneurons also expressed B7H6, the ligand for the activating receptor NKp30. In line with these observations, IL-2 stimulated NK cells showed robust cytotoxic responses to ES and iPS cells as well as to iPS cell-derived motoneurons. No significant differences in cytotoxicity levels were observed between KIR/HLA matched and mismatched combinations of NK cells and pluripotent targets. Together, these data indicate that pluripotent stem cells and their neural progeny are targets for NK cell killing both by failing to sufficiently express ligands for inhibitory receptors and by expression of ligands for activating receptors.

关键词： Anti-HLA antibodies prevalence   HLA   HLA-antibodies   Live related renal transplantation   SAB assay  

摘要： AIM:Detection of anti-HLA antibodies is crucial for pre-transplant histocompatibility testing, donor selection, and graft survival. The aim of this study was to evaluate the spectrum of anti-HLA antibodies among live related renal transplant recipients from one of the largest transplant centers in north India. METHODS:In this study, retrospective data of transplant workup done in past four years were analyzed using GraphPad Prism 9 Version 9.2.0 (La Jolla, CA, USA). All samples received for pre-transplant work-up if showed positive screening results underwent Luminex single antigen bead (L-SAB) assay. Antibodies identified on L-SAB were evaluated for their specificity and the strength of their mean florescence intensity (MFI). RESULTS:A total of 1250 renal transplant samples were included for analysis. Out of these, 458 (36.64 %) samples were found positive in screening tests algorithm. All 458 samples were further analyzed for both class I and class II HLA antibodies by Luminex single antigen bead (L-SAB) assay. In this study, we observed that anti-A*24:01, anti-B*15:01 and anti-C*07*01 were the three most prevalent anti-HLA antibodies identified against HLA-class I antigens. However, anti-DRB1*11:01, anti-DQA1*05:01-DQB1*03:01 and anti-DPA1*02:01-DPB1*17:01 were the most common anti-HLA antibodies identified against HLA-class II antigen. Furthermore, our study found a significant association between anti-HLA class I antibody and the history of pregnancy. However, in re-transplant cases, we observed the presence of antibodies both against HLA class I and II antigens. CONCLUSION:For a transplant center, it is of utmost importance to have comprehensive knowledge about the prevalence of HLA antibodies, their MFI, and their association with various sensitization events. This study may immensely help transplant communities in selecting appropriate prospective organ donors, planning desensitization regimes, managing recipients' care and predicting transplant outcomes in

关键词： IGF-1   IL-1 beta   LPS   microglia   neurodegenerative diseases   neuroinflammation   NLRP3   sex differences   TREM2  

摘要： BackgroundNeurodegenerative diseases (NDs) have caused serious health issues worldwide. A growing body of evidence suggests a correlation between neuroinflammation and abnormal microglial activity with ND symptoms. Microglia survey play crucial roles in CNS during health and the injury. It is proposed that sex affects microglial roles during inflammation, resulting in mouse behavioural changes and expression alterations in key markers related to microglia *** and female C57BL/6 mice were injected with a single dose of LPS (5 mg/kg, i.p.) or saline. After 48 h, an open field test was conducted, followed by brain tissues collection for measuring the expression of IGF-1, IL-1 beta and TREM2 and Immunohistochemistry (IHC) analysis for NLRP3 *** displayed greater depressive-like behaviour in the OFT, with lower levels of IGF-1, IL-1 beta, and NLRP3 and high TREM2 expression. Female mice did not exhibit this behaviour, in contrast to male mice, they exhibited increased IL-1 beta and NLRP3 expressionDiscussionThis study revealed that LPS-induced sex-specific changes in genes involved in neuronal cell survival caused behavioural alterations in male mice. Moreover, females had observed inflammatory responses that had no impact on behavioural alterations. Overall, both sexes exhibited sex-specific microglial activation states.

关键词： Anti-HLA antibodies   HLA-mismatches   Kidney Transplantation   Luminex   graft survival   repeat transplantation  

摘要： Repeat HLA mismatches (RMM) have been historically associated with an increased risk of graft loss after repeat kidney transplantation, in particular HLA-DR RMM in sensitized recipients. As routine use of sensitive assays can at present prevent the transplantation of RMM in hosts with donor-specific antibodies, we hypothesized that RMM would no longer be associated with graft loss. We performed a registry analysis of the Collaborative Transplant Study database including 6711 patients who received a second kidney transplant (2 KT) between 2010 and 2021, with at least one HLA-A, -B or -DR mismatch. No increased risk for graft loss was observed for 2 KT with a Class I RMM, regardless of sensitization status. For 2 KT with a HLA-DR RMM, the hazard ratio for graft loss in the first year after transplantation was 1.61 (95% CI 1.16 - 2.23; P=0.004) compared to recipients without a RMM, and increased to 2.21 (95% CI 1.24 - 3.63: P=0.002) in sensitized recipients (latest CDC-PRA>0%). Our observations suggest that Class I RMM do not need to be systematically avoided. In contrast, HLA-DR RMM still had a negative impact on graft survival in this contemporary cohort, despite the widespread availability of Luminex.

关键词： Alleles   HLA   HSCT   Haplotypes   Supertypes  

摘要： This retrospective study analyses the impact HLA heterozygosity, supertypes, and alleles have on incidence of graft versus host disease (GvHD), relapse, overall survival (OS), disease-free survival (DFS) and transplant-related mortality (TRM) after HSCT. The study included patients who underwent HSCT, typed at allele resolution level for HLA-A, B, C, -DRB1, -DQB1, and -DPB1 loci. The analysis performed on the entire patient cohort (N = 232) showed that HLA-B07 supertype positive patients demonstrated decreased incidence of relapse, better OS and DFS in comparison to those negative for HLA-B07 supertype. Further, a higher incidence of TRM was observed among patients positive for HLA-B27 supertype. Significant association of the HLA-A*02:01 allele presence with decreased incidence of GvHD was found. The occurrence of HLA-A*11:01 allele was associated with a worse OS, DFS and a higher rate of TRM. The analysis of the subgroup of patients with AML or MDS (N = 148) showed an association of HLA-A24 supertype with a worse OS. The HLA-B07 supertype positive patients demonstrated a lower incidence of relapse and a better DFS. A decline in OS and a higher TRM rate were observed among patients positive for HLA-B27 supertype. The presence of HLA-A*11:01 allele was indicative of a worse OS, DFS and a higher rate of TRM. The associations of HLA and HSCT clinical outcome parameters found in this study justify further investigation of this matter.

关键词： MC-LR   Apoptosis   TNF-R1   RIPK1   HEK293  

摘要： In recent years, the outbreak of cyanobacterial blooms has become increasingly frequent. Microcystin-LR (MC-LR), a metabolite of cyanobacteria, poses a significant threat to the ecosystem and human health. Several studies have demonstrated that MC-LR might induce renal cell apoptosis, as a consequence of tissue damage. However, the molecular mechanisms underlying MC-LR-initiated renal injury remain to be determined. This investigation aimed to determine the role of apoptosis in MC-LR-induced kidney damage and its potential underlying mechanisms using the human embryonic kidney (HEK293) cell line. The results of TUNEL and immunofluorescence assays indicated that MC-LR induced increased apoptosis in HEK293 cells. Compared to control, the mRNA expression levels of RIPK1, caspase-8, and TNF-alpha were elevated following incubation with MC-LR, while the mRNA expression level of Bcl-2/Bax was decreased. The protein levels of RIPK1, TNF-R1, and caspase-8 were elevated in the MC-LR-treated HEK293 cells. Data demonstrated that MC-LR induced renal cell apoptosis through activation of the TNF-R1/RIPK1 pathway, providing new insights into understanding the toxic mechanisms attributed to MC-LR.