Clinical and experimental immunology最新文献

Clinical manifestations, as distinct from thrombotic and obstetric morbidity, were recently included in the update of classification criteria of the antiphospholipid syndrome (APS). However, the existence of several patients with clinical manifestations suggestive of APS, but negative for criteria antiphospholipid antibodies (aPLs) [anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI), and lupus anticoagulant] may suggest an update of diagnostic criteria. In this study, we analysed the prevalence of six non-criteria aPLs in a large monocentric cohort of patients with seronegative APS (SN-APS), to investigate their possible diagnostic role. aCL IgA, aβ2-GPI IgA, and aβ2-GPI Domain 1 antibodies were detected by chemiluminescence, anti-phosphatidylserine/prothrombin (aPS/PT) IgG, anti-vimentin/cardiolipin (aVim/CL) IgG, and anti-carbamylated-β2-glycoprotein I (aCarb-β2-GPI) IgG by ELISA in sera from 144 SN-APS patients. In SN-APS patients, aCL IgA was detected in 4/144 (2.77%), aβ2-GPI IgA in 2/144 (1.39%), aβ2-GPI-Domain 1 in 1/144 (0.69%), aPS/PT in 16/144 (11.11%), aVim/CL in 37/144 (25.69%), and aCarb-β2-GPI in 43/144 patients (29.86%). Patients negative for all non-criteria aPL assays were 77/144 (53.47%). Notably, the Venn diagram showed that aCarb-β2-GPI together with aVim/CL represented the prevalent combination of positive antibodies. In SN-APS patients, aCL IgA were associated with recurrent thrombosis (OR 11.48; P = 0.03); in obstetric SN-APS patients, aPS/PT were significantly associated with foetal deaths (OR 4.84; P = 0.01), aVim/CL with spontaneous abortions (OR 2.71; P = 0.016). This study indicates that aPS/PT, aVim/CL and aCarb-β2-GPI antibodies may represent useful tools to identify 'seronegative' APS patients, who are negative for criteria aPLs, supporting the need to make testing for non-criteria aPLs more accessible in patients with SN-APS.

Neutrophil extracellular traps (NETs) released by neutrophils are web-like DNA structures adhered to granulin proteins with bactericidal activity and can be an important mechanism for preventing pathogen dissemination or eliminating microorganisms. However, they also play important roles in diseases of other systems, such as the central nervous system. We tracked the latest advances and performed a review based on published original and review articles related to NETs and neurological diseases. Generally, neutrophils barely penetrate the blood-brain barrier into the brain parenchyma, but when pathological changes such as infection, trauma, or neurodegeneration occur, neutrophils rapidly infiltrate the central nervous system to exert their defensive effects. However, neutrophils may adversely affect the host when they uncontrollably release NETs upon persistent neuroinflammation. This review focused on recent advances in understanding the mechanisms and effects of NETs release in neurological diseases, and we also discuss the role of molecules that regulate NETs release in anticipation of clinical applications in neurological diseases.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely related inflammatory disorders. Easily measurable biomarkers defining active disease and identifying patients in need of glucocorticoid sparing treatment options are highly desired. Interferon Type I (IFN-I) might be involved in disease pathology; however, evidence is limited. This study explores a systemic IFN-I signature and expression of IFN-I markers in GCA and PMR patients. Treatment naive GCA and PMR patients, and PMR patients with glucocorticoid treatment were included. Patients suspected of but not diagnosed with GCA were used as controls. Five relevant IFN-I-stimulated genes were identified in literature, and relative expression levels were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in peripheral blood mononuclear cells. An IFN-I score was generated. Serum levels of IFN-I induced C-X-C motif chemokine 10 (CXCL10) and Galectin-9 were determined by multiplex immunoassay. There were no differences in IFN-I scores between the groups. An IFN-I signature was observed in 0/9 controls, 2/11 GCA patients, 4/20 treatment naive PMR patients, and 2/10 PMR patients with treatment. Serum CXCL10 and Galectin-9 were not increased in GCA or PMR patients compared to control patients. Treated PMR patients had lower CXCL10 levels [423.2 pg/ml (375.1-491.1)] compared to treatment naive PMR patients [641.8 pg/ml (552.8-830.6)]. An IFN-I signature does not distinguish GCA and PMR patients from controls. Also, IFN-I-induced serum markers are not upregulated in GCA and PMR patients. Easily measurable IFN-I-induced serum markers will therefore probably not aid in diagnosis and additional treatment options in newly diagnosed GCA and PMR patients.

The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analyzed in two Brazilian patients with typical UBA1 mutations, and compared with healthy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood.

Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-related genes (ARGs) in psoriasis have not been systematically elucidated. Therefore, we aim to identify potential biomarkers and subtypes using two algorithmsr. Transcriptome sequencing data of patients with psoriasis were obtained, in which differentially expressed genes were assessed by principal component analysis. A diagnostic model was developed using random forest algorithm and validated by receiver operating characteristic (ROC) curves. Subsequently, we performed consensus clustering to calculate angiogenesis-associated molecular subtypes of psoriasis. Additionally, a correlation analysis was conducted between ARGs and immune cell infiltration. Finally, validation of potential ARG genes was performed by quantitative real-time PCR (qRT-PCR). We identified 29 differentially expressed ARGs, including 13 increased and 16 decreased. Ten ARGs, CXCL8, ANG, EGF, HTATIP2, ANGPTL4, TNFSF12, RHOB, PML, FOXO4, and EMCN were subsequently sifted by the diagnostic model based on a random forest algorithm. Analysis of the ROC curve (area under the curve [AUC] = 1.0) indicated high diagnostic performance in internal validation. The correlation analysis suggested that CXCL8 has a high positive correlation with neutrophil (R =0.8, P < 0.0001) and interleukins pathway (R = 0.79, P < 0.0001). Furthermore, two ARG-mediated subtypes were obtained, indicating potential heterogeneity. Finally, the qRT-PCR demonstrated that the mRNA expression levels of CXCL8 and ANGPTL4 were elevated in psoriasis patients, with a reduced expression of EMCN observed. The current paper indicated potential ARG-related biomarkers of psoriasis, including CXCL8, ANGPTL4, and EMCN, with two molecular subtypes.

Neutrophil extracellular traps (NETs) are associated with rheumatoid arthritis pathogenesis and severity. Since homeostatic NET-forming neutrophils [NET+Ns] have beneficial roles in defense against pathogens, their distinction from pro-injury [NET+N] subtypes is important, especially if they are to be therapeutically targeted. Having identified circulating, pro-injury DEspR+CD11b+[NET+Ns] in patients with neutrophilic secondary tissue injury, we determined whether DEspR+[NET+Ns] are present in rheumatoid arthritis (RA) flares. Whole blood samples of patients with RA flares on maintenance therapy (n = 6) were analyzed by flow cytometry (FCM) and immunofluorescence cytology followed by semi-automated quantitative confocal microscopy (qIFC). We assessed clinical parameters, levels of neutrophils and [NET+Ns], and plasma S100A8/A9. qIFC detected circulating DEspR+CD11b+neutrophils and [NET+Ns] in RA-flare patients but not healthy controls. DEspR+[NET+Ns] were positive for citrullinated histone H3 (citH3+), extruded DNA, decondensed but recognizable polymorphic nuclei, and [NET+N] doublet interactions in mostly non-ruptured NET-forming neutrophils. Circulating DNA+/DEspR+/CD11b+/citH3+microvesicles (netMVs) were observed. FCM detected increased %DEspR+CD11b+neutrophils and DEspR+ cell-cell doublets whose levels trended with DAS28 scores, as did plasma S100A8/A9 levels. This study identifies circulating DEspR+/CD11b+neutrophils and [NET+Ns] in RA-flare patients on maintenance therapy. Detection of circulating DEspR+citH3+[NET+Ns] and netMVs indicate a systemic neutrophilic source of citH3-antigen concordant with multi-joint RA pathogenesis. Increased S100A8/A9 alarmin levels are associated with cell injury and released upon NET-formation. As a ligand for TLR4, S100A8/A9 forms a positive feedback loop for TLR4-induced DEspR+neutrophils. These data identify DEspR+neutrophils and [NET+Ns] in RA pathogenesis as a potential biomarker and/or therapeutic target.

Our ability to understand the cellular complexity of tissues has been revolutionized in recent years with significant advances in proteogenomic technologies including those enabling spatial analyses. This has led to numerous consortium efforts, such as the human cell atlas initiative which aims to profile all cells in the human body in healthy and diseased contexts. The availability of such information will subsequently lead to the identification of novel biomarkers of disease and of course therapeutic avenues. However, before such an atlas of any given healthy or diseased tissue can be generated, several factors should be considered including which specific techniques are optimal for the biological question at hand. In this review, we aim to highlight some of the considerations we believe to be important in the experimental design and analysis process, with the goal of helping to navigate the rapidly changing landscape of technologies available.

Ongoing therapeutic advances in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) have significantly reduced the risk of death in AAV, but 30%-50% of patients still relapse. Relapse is a major problem in these diseases, leading to increased morbidity and mortality. It is, therefore, necessary to find predictors of relapse at the end of the remission induction and maintenance phases in order to personalize treatment.

Prevention and treatment of infections are primary goals of treatment of children and adults with primary immune deficiencies due to decreased antibody production. Approaches to these goals include immunoglobulin replacement therapy, vaccination, and prophylactic treatment with antimicrobials. In this review, the infectious and non-infectious complications of antibody deficiencies will be discussed along with the limited number of studies that support the effective use of the available therapies and to drive the development of new therapies. Some illustrative case studies will be presented and the outlook for additional controlled clinical trials and potential for therapies driven by the underlying disease genetics will be considered.

Preclinical data suggest that type I interferon (IFN) responsiveness is essential for the antitumor effects of radiotherapy (RT). However, its clinical value remains unclear. This study aimed to explore this from a clinical perspective. In cohort 1, data from 152 hepatocellular carcinoma (HCC) patients who received RT were analyzed. Blood samples were taken 1 day before and 2 weeks after RT. RT was found to increase serum levels of IFN-β (a subtype of IFN-I) in HCC patients (3.42 ± 1.57 to 5.51 ± 2.11 pg/ml, P < 0.01), particularly in those with favorable responses. Higher post-RT serum IFN-β levels (≥4.77 pg/ml) were associated with better progression-free survival (HR = 0.58, P < 0.01). Cohort 2 included 46 HCC patients, including 23 who underwent preoperative RT and 23 matched control HCC who received surgical resection without RT. Formalin-fixed paraffin-embedded samples were obtained. Neoadjuvant RT significantly increased IFN-β expression in tumor tissues compared to direct surgery (8.13% ± 5.19% to 15.10% ± 5.89%, P < 0.01). Higher post-RT IFN-β (>median) indicated better disease-free survival (P = 0.049). Additionally, increased CD11c+MHCII+CD141+ antigen-presenting cell subsets and CD103+CD39+CD8+ tumor-infiltrating lymphocytes were found in the higher IFN-β group (P = 0.02, P = 0.03), which may contribute to the favorable prognosis in higher IFN-β group. Collectively, these findings suggest that IFN-β response activated by radiation may serve as a prognostic biomarker for HCC patients undergoing RT.