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关键词： HLA   HLA-DQA1*01:02:24   novel allele   sequencing-based typing  

摘要： HLA-DQA1*01:02:24 differs from HLA-DQA1*01:02:01:03 by one nucleotide substitution in codon 167 in exon 3.

关键词： Calves   High mobility group box-1   MX dynamin-like GTPase 1   Systemic inflammatory index   Systemic inflammation response index   Tumor necrosis factor  

摘要： The objective of this study was to examine the values of MX dynamin-like GTPase 1 (Mx1), high mobility group box-1 (HMGB1), systemic inflammatory response index (SIRI), systemic inflammatory index (SII), tumor necrosis factor (TNF), and other hematological indices in calves with systemic inflammatory response syndrome (SIRS). The study material was divided into two groups: the SIRS group (comprising 13 calves) and the control group (comprising 10 calves). The independent samples t-test and Mann-Whitney U test were employed for normally distributed and non-normally distributed data, respectively. The relationship between the two groups was determined using Spearman correlation coefficient analysis. Significant differences were identified between the SIRS group and the control group with regard to white blood cell (WBC;P G 0.05), neutrophil (NEU;P G 0.01), and neutrophil-to-lymphocyte ratio (NLR;P G 0.001) values, in addition to SIRI (P G 0.05), SII (P G 0.01) values. Furthermore, HMGB1 (P G 0.001), Mx1 (P G 0.05), and TNF values (P G 0.001) demonstrated notable disparities between the two groups. As a result of this study, it was concluded that there were significant increases in inflammatory hematological indices, as well as in the levels of HMGB1, Mx1, and TNF, in calves with SIRS.

关键词： epitope discovery   mass spectrometry   Listeria monocytogenes   bacterial infection   MHC  

摘要： Listeria monocytogenes is a foodborne intracellular bacterial model pathogen. Protective immunity against Listeria depends on an effective CD8(+) T cell response, but very few T cell epitopes are known in mice as a common animal infection model for listeriosis. To identify epitopes, we screened for Listeria immunopeptides presented in the spleen of infected mice by mass spectrometry-based immunopeptidomics. We mapped more than 6000 mouse self-peptides presented on MHC class I molecules, including 12 high confident Listeria peptides from 12 different bacterial proteins. Bacterial immunopeptides with confirmed fragmentation spectra were further tested for their potential to activate CD8(+) T cells, revealing VTYNYINI from the putative cell wall surface anchor family protein LMON_0576 as a novel bona fide peptide epitope. The epitope showed high biological potency in a prime boost model and can be used as a research tool to probe CD8(+) T cell responses in the mouse models of Listeria infection. Together, our results demonstrate the power of immunopeptidomics for bacterial antigen identification.

关键词： circPHF16   miR-378a-3p   IL6ST   Graves' disease  

摘要： Interleukin-17A (IL-17A) plays a pivotal role in the pathogenesis of Graves' disease (GD), an autoimmune disorder affecting thyroid function, but the detailed regulatory mechanisms remain elusive. Circular RNAs (circRNAs) have emerged as key regulators of IL-17A expression and secretion in autoimmune diseases, yet their specific role in GD, especially within CD4 + T lymphocytes, are not well understood. In this study, a circRNA, circPHF16 (hsa_circ_0090364) was found to be highly expressed in the peripheral blood mononuclear cells and serum of GD patients. In vitro experiments in Jurkat T cells revealed that silencing of circPHF16 suppressed IL17A expression and secretion, while overexpression of circPHF16 had the opposite effect. Furthermore, bioinformatics analysis demonstrated a circPHF16/miR-378a-3p/IL6ST pathway, in which circPHF16 regulates IL6ST expression, which, in turn, influences IL-17A expression and secretion by interacting with miR-378a-3p. In vivo studies in a mouse model of GD showed similar trends in molecular expression levels, consistent with competitive endogenous RNA interactions. Together the results of the study identify circPHF16 as a potential target in the development of new strategies for GD diagnosis and treatment, and thus, offer a theoretical foundation for clinical therapeutic approaches in GD.

关键词： anti-inflammatory macrophages   engineered probiotics   Escherichia coli Nissle 1917   inflammatory bowel disease   propionate synthetic biology  

摘要： Inflammatory bowel disease (IBD) is a chronic and unspecific inflammatory disorder of the gastrointestinal tract, and current treatment options often fail to maintain long-term remission. Studies have shown that propionate level is reduced in fecal samples from patients with IBD. Propionate can ameliorate IBD through intestinal epithelial cells and immune regulation, but its effects on the inflammatory microenvironment and macrophage differentiation have not been widely studied. To address this, we constructed an engineered propionate-producing probiotic (EcNP3) to achieve sustained restoration of propionate levels in the gut and increase its bioavailability. DSS-induced experimental intestinal inflammation model was used to evaluate the effect of EcNP3 on improving the intestinal mucosal barrier and increasing the proportion of anti-inflammatory macrophages. It was found that EcNP3 exhibited a restorative effect on the depletion of peritoneal anti-inflammatory macrophages (F4/80hiCD11bhi) and significantly improved the expression level of IL-10. Simultaneously, the expression of IL-1 beta, IL-6, and CXCL1 was downregulated while inhibiting apoptosis of tissue-resident macrophages ex vivo. Further investigation revealed that EcNP3 regulates IL-10 expression through G protein-coupled receptor 43 and histone deacetylase. Furthermore, EcNP3 significantly inhibited the protein expression of HDAC1 and promoted the histone acetylation level of cells. Finally, EcNP3 significantly improved DSS-induced colitis in mice by increasing mucus production and reducing inflammatory infiltration. Our results suggest that the engineered live biotherapeutic product EcNP3 is a safe and potently efficacious treatment for IBD, which defines a novel strategy in IBD therapy through macrophage IL-10 signaling.

关键词： Chronic inflammation   NFAT1   Psoriasis   Myeloid derived cells   T cells   ROR gamma t  

摘要： Objective and design The exact immunological mechanism of widespread chronic inflammatory skin disorder psoriasis has not been fully established. CD11b(+)Gr.1(+) myeloid-derived cells are immature heterogeneous cells with T-cell suppressive property in neoplasia;however, influence of these cells on adaptive immunity is highly contextual;therefore, we dubbed these cells as myeloid-derived adjuster cells (MDAC). We studied imiquimod induced psoriasis in mouse model and evaluated for the first time the ROR gamma t-NFAT1 axis in MDACs and the function, differentiation and interaction of these cells with T cells. Materials and methods The status of T cells and MDACs;their functionality and differentiation properties, and the roles of ROR gamma t and NFAT1 in MDACs were evaluated using flow cytometry, qRT-PCR and confocal imaging. Results We found gradual increase in T cells and MDACs and an increase in the number of IL17 -secreting MDACs and T cells in the skin of psoriatic animals. We also noted that MDAC differentiation is biased toward M1 macrophages and DCs which perpetuate inflammation. We found that psoriatic MDACs were unable to suppress T-cell proliferation or activation but seemingly helped these T cells produce more IL17. Inhibition of the ROR gamma t/NFAT1 axis in MDACs increased the suppressive nature of MDACs, allowing these cells to suppress the activity of psoriatic T-cells. Conclusion Our results indicate that altered MDAC properties in psoriatic condition sustains pathological inflammation and ROR gamma t and NFAT1 as promising intervention target for psoriasis management.

关键词： donor-dominant one-way HLA match   graft-versus-host disease   liver transplantation   living donor  

摘要： Aims To study the effects of routine HLA screening and the policy of avoiding donor-dominant one-way HLA match to prevent graft-versus-host disease (GVHD) after living donor liver transplantation (LDLT). Patients and Methods The records of potential living liver donors and recipients who attended our center between 2007 and 2018 were reviewed retrospectively. Results Of the 149 patients who underwent LDLT and survived longer than 3 months, two developed GVHD despite our strict policy. The first patient presented with grade II GVHD limited to the skin. She was treated successfully by briefly discontinuing immunosuppression and switching to everolimus. In the second case, the policy had been relaxed due to the availability of a single donor for ABO-incompatible transplantation without any intervention to decrease anti-A antibody levels (special case: A2 to O). Nevertheless, the patient presented with grade I GVHD limited to skin and was treated successfully by adding oral methylprednisolone to tacrolimus and mycophenolate mofetil. To the best of our information, this is the second reported case who recovered from GVHD after LDLT from a donor, homozygous at HLA A, B and DR and a recipient, heterozygous for all. Sixteen potential donors (1.2% of all candidates) of 14 recipients were disqualified solely on the basis of the HLA results;five of these patients died due to unavailability of another donor. Conclusion The results support the policy of avoiding HLA combinations that preclude immune recognition of graft lymphocytes as foreign to decrease the risk of GVHD after LDLT.

摘要： Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4(+) T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4(+) T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4(+) T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events.

关键词： HIV   SARS-CoV-2   mRNA vaccine   inactivated vaccine   anti-SARS-CoV-2 RBD IgG  

摘要： The safety of the mRNA and inactivated SARS-CoV-2 vaccine has been demonstrated for people living with HIV (PLHIV). However, vaccine studies in PLHIV are limited, and there is a gap in which vaccine type provides the best response in PLHIV. Thus, PLHIV may benefit from mRNA vaccine types compared to inactivated vaccines. This study aims to assess the immune responses to vaccination by measuring specific antibodies (IgG) targeting the receptor binding sites (RBDs) of the SARS-CoV-2 virus and the levels of IL-2 and IFN-gamma in plasma. A total of 41 PLHIV who regularly take antiretroviral therapy (ART) over a period of six months, along with 31 individuals in a healthy control group (HC), were administered either two mRNA or inactivated vaccines. Data regarding demographics and clinical information were gathered from the medical records. An analysis was conducted on the neutralisation antibody IgG specific to RBD using the chemiluminescence microparticle assay (CMIA). The levels of IL-2 and IFN-gamma were quantified using the Luminex assay method from plasma samples. Data were collected in the laboratory 28 days after each vaccination. After the first vaccination, the level of anti-SARS-CoV-2 RBD IgG was higher in PLHIV who received the mRNA vaccines than those who received inactivated vaccines (p = 0.006). The levels of mRNA in the PLHIV group showed a significant correlation with IL-2 and IFN-gamma after the second vaccination (r = 0.51, p = 0.0035;r = 0.68, p = 0.002). The group of PLHIV who received the inactivated vaccine showed increased IL-2 and IFN-gamma after the initial vaccination, compared to PLHIV who received the mRNA vaccine (p = 0.04;p = 0.08). Administering a two-dose vaccination is essential to increase the levels of neutralising antibodies significantly (p = 0.013) in PLHIV who have received inactivated vaccines;further study is needed to make this a recommendation. The responses observed after vaccination in PLHIV were not affected by their CD4 cel

关键词： HIV-1   Interleukin-10   SNP   Viral load   Lymphocyte  

摘要： The risk of HIV-1 infection and the rate of disease progression vary considerably among individuals and the genetic makeup of the host may be one of the possible reasons for this. We aimed to determine association of functional single nucleotide polymorphism (SNPs), -1082A/G (rs1800896), -819C/T (rs1800871), and -592C/A (rs1800872) in IL-10 gene, with the susceptibility to HIV-1 infection and clinical parameters expressed as a baseline CD4+ T cell count, CD8+ T cell count, and viral load. Therapy na & iuml;ve HIV-1 infected individuals and HIV-1 seronegative controls from Poland were recruited for this study. Genotyping results revealed significantly higher frequency of -1082G/G genotype (28.1 % vs 16.1 %;p = 0.0019, OR=0.49) and -1082G allele (47.6 % vs 38.8 %;p = 0.0028, OR = 0.70) as well as lower frequency of -592 and -819 heterozygosity (45.0 % vs 34.4 %;p = 0.0266, OR = 1.47) in controls compared to seropositive subjects. High producing haplotype GCC was associated with increased risk of HIV-1 infection (p = 0.0018, OR = 1.52). Individuals possessing -592 and -819 minor allele had significantly higher CD8+ T cell count compared to the wild type allele carriers (p = 0.0303). Moreover, presence of -1082G allele was related with lower viral load as well as CD4+ and CD8+ T cells counts among patients infected with R5 HIV-1 variant. Thus, IL-10 gene promoter variants may be a risk factor for HIV-1 transmission and may modulate disease progression in the Polish population.