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关键词： MHC   ORF8   Nsp1  

摘要： Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-gamma (IFN-gamma)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-gamma-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-gamma-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition.

关键词： diversity   genetics   haematopoietic cell transplant   italic>HLA-E   non-classical HLA  

摘要： HLA-E is a non-classical HLA class I gene with limited reported genetic variability and few published studies into full-gene sequencing or population allele frequencies. Two protein variants, HLA-E*01:01 and HLA-E*01:03, are very common, accounting for 94%-100% of observed alleles in most studies performed to date. Frequently utilised exon-based sequencing strategies have led to the assumption of HLA-E being a near bi-allelic gene;however, recent full-gene sequencing studies have shown a greater degree of genetic variability than initially imagined. We carried out a literature review of HLA-E genotype and ethnicity data, which suggested HLA-E*01:03 is more common in Asian and, in particular, East Asian populations. Furthermore, HLA-E*01:03:02 is more frequently observed than HLA-E*01:03:01 in European and American populations, whereas HLA-E*01:03:01 is found at higher frequencies in Asian populations. It has been proposed that HLA-E may have a role in Haematopoietic Cell Transplantation (HCT) due to its interaction with NK and CD8+ T cells and its non-canonical peptide binding repertoire. Here we also review published literature into the effects of HLA-E genetics on HCT outcomes. Heterogeneity between cohorts muddies the waters;hence, studies report confounding effects of HLA-E genotype and matching on HCT outcomes. The need for further HLA-E sequencing of larger cohorts is evident to gain useful insight into the true genetic variability of HLA-E and its impact on HCT.

关键词： Sepsis   IFN gamma   Hyperinflammation   Immunosuppression   Immunosuppressive therapy   Immunostimulatory therapy  

摘要： BackgroundThe cytokine IFN gamma is released primarily by lymphocytes to initiate and orchestrate immune responses in a broad range of target cells. Whereas immune cells release inflammatory mediators and initiate antimicrobial responses when stimulated by IFN gamma, parenchymal cells frequently display increased immunogenicity and incidental cell death. In addition to these well-characterized effects of IFN gamma, recent studies disclose a key role of the cytokine in sepsis and organ *** review summarizes current knowledge on the IFN gamma response to infection and attempts to relate the IFN gamma response to endophenotypes of sepsis in the human host. Both, excessive pro-inflammatory responses with high IFN gamma and downstream mediators, such as chemokines (CXCL9), as well as immunosuppression with low IFN gamma levels are associated with unfavorable outcomes in sepsis. Pilot studies suggested beneficial effects of recombinant IFN gamma in counteracting immunosuppression associated with low IFN gamma levels. On the other hand, IFN gamma may induce macrophages to release chemokines CXCL9, 10, and 11 to attract B and T lymphocytes to the sites of infection. Downstream induction of CXCL9 (but not of CXCL10 and 11) occurring in a subset of patients with high IFN gamma levels has been shown to correlate with the hyper-inflammatory phenotype of sepsis. Both, high- and low-expressing IFN gamma phenotypes of sepsis, might be related to nucleotide polymorphisms of the human IFN gamma *** of IFN gamma activity states with sepsis outcome renders this key regulatory protein of immunity a top candidate for theranostic interventions in a "personalized medicine approach" to infection and sepsis, especially when combined with additional biomarkers, such as CXCL9, reflecting or even mediating maladaptive downstream actions.

关键词： HLA-C*03:714   NGS-based typing   novel allele  

摘要： HLA-C*03:714 differs from HLA-C*03:04:01:01 by one nucleotide substitution at position 685G>A in exon 4.

关键词： Repetitive mild traumatic brain injury (rmTBI)   Interleukin-33 (IL-33)   Microglia   Cognition  

摘要： BackgroundRepetitive mild traumatic brain injury (rmTBI) is a significant risk factor for neurodegeneration, characterized by pathological protein deposition and persistent neuroinflammation. Research has observed increased interleukin-33 (IL-33) levels in the peripheral blood of patients with rmTBI, suggesting IL-33 may participate in regulating the pathological development of rmTBI. The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI, and to explore its potential as a therapeutic target to improve the neurological *** study employed an rmTBI mouse model using the wild-type (WT) and IL-33 knockout mice. Cognitive function was assessed via the Y-maze and Barnes tests. The main cell type expressing IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), was then investigated in the mouse brain through immunofluorescence colocalization. As the primary neural cell responsible for ST2 expression, microglia were studied in vitro using the BV2 cell line. The effects of lipid droplets (LDs) accumulation and amyloid-beta (A beta) phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells' phagocytosis. Additionally, HT22 neuronal apoptosis was assessed by flow cytometry. Finally, the cognitive effects of intranasal administration of IL-33 were evaluated in ***-33KO mice exhibited pronounced cognitive impairment after rmTBI. In the mouse brain, astrocytes were identified as the primary source of IL-33 secretion, while microglia predominantly expressed ST2. Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function. IL-33 mitigated LDs accumulation in BV2 cells and enhanced A beta phagocytosis in vitro. In addition, the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage. Furthermore, intranasal administration of IL-33 was observed to be effective in alleviating neurodegenera

关键词： HTLV-I infection   inflammatory diseases   toll-like receptor 3   polymorphism genetic   cytokines  

摘要： Introduction Alterations in the immune response may influence the development of HTLV-1-associated diseases. TLR3 detects viral nucleic acids, including HTLV-1, and triggers the production of IFN-I and other cytokines. Genetic variations in TLR3 may alter the antiviral and inflammatory responses and contribute to the progression of HTLV-1 infection. The present study investigated the association of polymorphisms in the TLR3 gene (rs5743305 T/A and rs3775291 C/T) with HTLV-1 infection status and their relationship with infection-associated diseases, receptor expression levels, proviral load, and inflammatory and antiviral *** Blood samples were collected from 179 individuals with HTLV-1 infection (82 with inflammatory diseases and 97 asymptomatic individuals) and 179 controls. Genotyping of polymorphisms, analysis of TLR3 gene expression, and quantification of proviral load were performed by real-time PCR, and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA).Results The polymorphisms showed no correlation with susceptibility to HTLV-1 infection, or the occurrence of disease symptoms linked to the infection. The presence of disease symptoms was associated with higher TNF-alpha levels and proviral load. TLR3 rs5743305 T/A polymorphism was not associated with variations in TLR3 and IFN-alpha levels. For the TLR3 rs3775291 C/T polymorphism, asymptomatic individuals carrying the TT polymorphic genotype presented significantly higher IFN-alpha levels and lower proviral load. The profile of asymptomatic individuals carrying the polymorphic genotypes for TLR3 rs3775291 C/T was characterized by higher levels of TLR3 and IFN-alpha and lower levels of proviral load, TNF-alpha and IL-6 compared to those with the wild-type *** Although polymorphisms in the TLR3 gene have not been associated with the presence of symptoms of HTLV-1-related inflammatory diseases, the TLR3 rs3775291 C/T polymorphism appears to contribute to a be

关键词： leishmaniasis   mucosa   italic>L. amazonensis   BALB/c   experimental infection  

摘要： Mucosal Leishmaniasis is one of the most aggressive clinical manifestations of Leishmania infection disease, characterized by the destruction of nasal and oral tissues. The mechanisms by which this disease occurs are still not well understood due to the lack of effective experimental models. Mucosal leishmaniasis is associated with inflammatory response, especially Th17 response. Based on that, in this work, the immunopathological aspects of the experimental infection of BALB/c mice by Leishmania amazonensis in the mucosa site were evaluated as this mice presents high susceptibility with increased Th17 mediated pathology. Three infection modes were performed and compared according to the injection site. Six weeks post infection, mice presented edema in the nasal and premaxillary region, with progressive growth until twelve weeks. The micro-Computerized Tomography and the histology images demonstrated that the parasite inoculation led to destruction of squamous and transitional tissues in NC and NB groups, with several cells harboring amastigotes. Mice infected in the mucosa tissues had higher parasite load and IgG, IgM antibody levels and increased production of cytotoxic mediators such as CD107, granzyme b and perforin, inflammatory cytokines as IFN-gamma;and IL-17, but lower frequencies of CD4+ IL-10+ cells compared to ear dermis. Taken together, our data shows that L. amazonensis parasites are more proliferative in nasal mucosa and the infection leads to an increased inflammatory response compared to ear dermis, suggesting an imbalance between the inflammatory and regulatory response in the mucosa as occurs in human MCL which point this model as an interesting approach to understand some features of the disease immunopathology. Further studies are being performed to understand the Th1-mediated tissue destruction. This study was conducted in accordance with the local legislation and institutional requirements being approved by the Ethics Committee on the Animal Us

关键词： inflammatory bowel disease   tofacitinib   tumour necrosis factor-alpha inhibitors   ulcerative colitis   vedolizumab  

摘要： Background: Management of refractory ulcerative colitis (UC) unresponsive to advanced therapies is challenging. Combination therapy is a potential strategy. Aim: To evaluate the safety and efficacy of vedolizumab and tofacitinib combination (VETO) therapy in patients with UC refractory to anti-TNF and unresponsive to either agent as monotherapy. Methods: We prospectively recruited patients with moderate-to-severe disease activity (Mayo score: 6-12). Patients were randomised to receive vedolizumab or tofacitinib. Non-responders were offered VETO therapy and followed for 24 weeks. The primary outcome was a combined clinical response and corticosteroid-free remission at week 24. Secondary outcomes included clinical response and remission at week 8, endoscopic remission at week 24 and incidence and severity of treatment-related adverse events. Results: Of 91 patients, 38 were randomised to vedolizumab and 40 to tofacitinib. Fourteen and 15, respectively, were non-responders to vedolizumab and tofacitinib;24 received VETO with follow-up of 34 +/- 16.1 weeks. Median second-line therapy duration before VETO was 21 weeks. Five non-responders received alternative interventions or were lost to follow-up. At week 8, 17 achieved clinical response and five achieved remission;three underwent colectomy. At week 24, response and corticosteroid-free remission were seen in 17 and 14, respectively;7 achieved endoscopic remission. Mayo scores improved significantly (mean difference 5.33 +/- 0.53;p < 0.01). Two patients developed pseudomembranous colitis that resolved with vancomycin. No severe adverse events occurred. Conclusion: VETO was effective and safe in patients with UC refractory to anti-TNF and second-line therapies, with over half achieving clinical remission by 24 weeks.

关键词： IL-17   inflammation   psoriatic arthritis   Th17   secukinumab   ixekizumab   bimekizumab   brodalumab  

摘要： IntroductionPsoriatic arthritis (PsA) is an immune-inflammatory disease involving skin and synovial-entheseal compartments. The understanding of IL-17 biological function has revolutionized the understanding of PsA pathogenesis and, consequently, its therapeutic *** coveredIn this review article, we have outlined the primary evidence regarding the biological functions of IL-17A in PsA, and summarized data from randomized controlled trials (RCTs) on PsA and psoriasis approved secukinumab, ixekizumab, bimekizumab, brodalumab, and emerging IL-17 *** opinionThe biologic disease-modifying antirheumatic drugs (bDMARDs), secukinumab, and ixekizumab target interleukin-17A (IL-17A), and bimekizumab, which simultaneously neutralizes IL-17A and IL-17F, have demonstrated efficacy in treating both peripheral and axial articular manifestations of PsA, as well in improving skin involvement, enthesitis and dactylitis. Brodalumab, which inhibits the IL-17 receptor A (IL-17RA), represent an efficacious strategy for *** research into the role of IL-17s in PsA pathogenesis is crucial for improving our understanding of the disease and developing more effective therapeutic strategies. Further research and advancements in biologic therapies will refine IL-17 inhibitory strategies, potentially improving outcomes for PsA patients, and other immune-mediated *** opinionThe biologic disease-modifying antirheumatic drugs (bDMARDs), secukinumab, and ixekizumab target interleukin-17A (IL-17A), and bimekizumab, which simultaneously neutralizes IL-17A and IL-17F, have demonstrated efficacy in treating both peripheral and axial articular manifestations of PsA, as well in improving skin involvement, enthesitis and dactylitis. Brodalumab, which inhibits the IL-17 receptor A (IL-17RA), represent an efficacious strategy for *** research into the role of IL-17s in PsA pathogenesis is crucial for improving our understanding of the diseas