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关键词： Disease-modifying Drugs (DMARDs)   Remission   Cytokines and Chemokines   Biomarkers   Adaptive immunity  

摘要： Background: Little is known of the factors that trigger disease relapses/flares in patients with rheumatoid arthritis (RA). These mechanisms have been difficult to study due to the unpredictable nature of flare. The BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (BIO-FLARE) study [1] is an experimental medicine study of ‘synchronised' RA flares in which treatment is withdrawn in RA patients in clinical remission receiving conventional synthetic (cs)DMARDs. Subsequently, approximately 50% flare within 6 months, the remainder maintaining drug-free remission (DFR). Objectives: We have assessed, longitudinally, circulating T cell subsets and mediators following treatment cessation, to better under the mechanisms driving flare and maintaining DFR. Methods: Individuals with RA receiving methotrexate, sulfasalazine and hydroxychloroquine, singly or in combinations, in clinician-defined remission with a DAS28-CRP <2.4 were recruited into BIO-FLARE. Treatment was stopped and participants monitored over 24 weeks, with serum and Smart Tube-fixed peripheral blood stored at 0, 2, 5, 8, 12 and 24 weeks. Flare was defined as DAS28-CRP ≥3.2 at any study visit, or DAS28-CRP ≥2.4 on two occasions within a 14-day period. Soluble serum mediators were detected by the NULISAseq Inflammation Panel 250 (Alamar Biosciences) [2]. Following data normalisation and quality control, differential expression analysis was performed comparing flare and DFR at baselines, as well as longitudinal analysis. Circulating T cell subsets were assessed using a 16 marker Phosflow panel. Results: At baseline, participants who subsequently flared and those who maintained DFR were well matched clinically, except for RF/ACPA titres, which were higher in those who subsequently flared. In contrast, NULISAseq analysis revealed differences in a number of inflammatory mediators, such as CXCL13 and soluble PD-1 (PDCD1), and immunoregulatory molecules, such as soluble CD83 and CTLA-4, all of w

关键词： biomarkers   ELISA   HSP90 alpha   IL-17 inhibitors   LC-MS/MS   non-radiographic axial spondyloarthritis   serotransferrin  

摘要： BackgroundNon-radiographic axial spondyloarthritis (nr-axSpA) is an early stage of axial spondyloarthritis characterized by the absence of definitive radiographic changes. Interleukin-17 inhibitors (IL-17i) have shown efficacy in treating nr-axSpA, but a significant proportion of patients fail to respond. Identifying predictive biomarkers for IL-17i response is crucial for optimizing treatment *** retrospective study analyzed pre-treatment serum samples from nr-axSpA patients treated with secukinumab. Responders (R) and non-responders (NR) were defined based on changes in ASDAS-CRP scores after 12 weeks of therapy. Serum protein profiles were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with label-free quantification, followed by validation of candidate proteins using enzyme-linked immunosorbent assay (ELISA). Statistical analyses included Student's t-test, Mann-Whitney U-test, and Spearman's ***-MS/MS identified 47 differentially expressed proteins (DEPs) between R and NR groups, with 31 upregulated and 16 downregulated in NR. Seven proteins including heat shock protein HSP 90-alpha (HSP90 alpha) and serotransferrin were selected for ELISA validation. ELISA confirmed significantly higher HSP90 alpha (p = 0.027) and lower serotransferrin (p = 0.034) levels in NR compared to R. HSP90 alpha showed a mild negative correlation with the reduction of BASDAI scores (r = -0.30, p = 0.035), while serotransferrin exhibited a mild positive correlation (r = 0.287, p = 0.048). Both proteins correlate mildly with the disease activity *** levels of HSP90 alpha and serotransferrin may serve as potential biomarkers for predicting IL-17i treatment response in nr-axSpA patients. Elevated HSP90 alpha and reduced serotransferrin levels may reflect chronic inflammation and disease activity, particularly from a subjective symptom perspective. Further validation in prospective studies is needed to confirm th

摘要： Novel alleles HLA-A*68:326 and -C*02:254N carry exonic mutations causing amino acid change or truncation.

关键词： COVID-19   Long COVID   HLA   KIR   Vaccination  

摘要： Background: The COVID-19 pandemic has led to widespread infection, with a significant subset of patients developing persistent symptoms known as Long COVID. Understanding the genetic factors influencing Long COVID susceptibility and severity is crucial for development of targeted interventions. Objective: This study aimed to evaluate the impact of HLA alleles, KIR receptors, and their interactions on the development of Long COVID in patients from southeastern Spain having contracted COVID-19 during the early 2020 pandemic wave. Methods: A cross-sectional prospective study enrolled 153 COVID-19 patients. Three months post-infection, HLAA, -B, -C, KIR genotyping and immunological variables were analyzed using serum and blood samples. Long COVID was diagnosed three years post- infection based on persistent symptoms. Results: Among the participants, 71 developed Long COVID. HLA-A*03 was less frequent in Long COVID compared to non-Long COVID patients (10.7 % vs. 30.5 %, p = 0.001). Patients with HLA-A*03 had a higher percentage of CD8+ T cells than patients with other allotypes (33.6 f 13.4 % vs 28.7 f 10.8 %, p = 0.033) and showed lower expression of KIR2DL1(1265 f 547 vs 1465 f 414 MFI, p = 0.031) and KIR3DL1 (300.6 f 125.0 vs 398.9 f 131.0 MFI, p = 0.047). Moreover, NK cells in HLA-A*03 patients showed lower expression of the TIGIT inhibitory receptor (73.7 f 12.2 % vs 78.2 f 10.8 %, p = 0.046). Conclusion: HLA-A*03 may play a protective role against Long COVID, potentially through enhanced immune responses involving CD8+ T cells and NK cells. Further research in larger, diverse cohorts is needed to validate these findings and to refine personalized medicine strategies for managing COVID-19 sequelae.

关键词： HLA   immune checkpoint inhibitor   lymphocyte   oral cancer   PD-L1  

摘要： Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers, and immunotherapy targeting programmed cell death 1 (PD-1) has become a treatment option for recurrent OSCC after surgery and radiation therapy. However, few studies have identified definitive biomarkers for predicting patient response to anti-PD1 therapy in OSCC. In the present study, biopsy specimens were obtained from 23 patients with recurrent OSCC who were subsequently treated with anti-PD1 therapy. Immunohistochemical examinations of CD3, CD8, FOXP3, CD103, CD163, programmed cell death ligand 1 (PD-L1), HLA-A/B/C, HLA-DR, and beta 2 microglobulin were performed, and their correlation with clinical response was statistically analyzed. We found that an increased density of CD8-positive lymphocytes and increased PD-L1 expression predicted a favorable response to anti-PD1 therapy in recurrent OSCC. In contrast, clinical factors such as age and sex, and immune-related factors such as HLA-Classes I and II, were not associated with the response to anti-PD1 therapy. Taken together, our results suggest that immunohistochemical analysis of CD8 and PD-L1 may be useful for predicting the efficacy of anti-PD1 therapy in recurrent OSCC.

关键词： Fluorouracil   Oleuropein   Inflammation   Heart   Lung   Oxidative stress  

摘要： The cardiac and lung damage are considered a serious risk associated with the administration of chemotherapy agents like 5-fluorouracil (5-FU). Oleuropein (OLE) is valuable medicinal plant that has diverse pharmacological properties with remarkable antioxidant activities. This research aimed to evaluate the impact of OLE on cardiac and pulmonary toxicity induced by 5-FU. 24 adult rats were randomly assigned to four groups (N = 6), which included a control group, a group receiving 5-FU at a dosage of 100 mg/kg, a group administered OLE at 200 mg/kg, and a group treated with both 5-FU and OLE (5-FU + OLE). Following the treatment, blood samples were obtained for the assessment of biochemical parameters, and the cardiac and pulmonary tissues were removed for the measurement of oxidative stress and inflammatory cytokines and histological alterations. 5-FU elevated lipid profiles (triglyceride, low-density lipoprotein (LDL), and cholesterol), glucose serum levels, and myocardial injury markers (CK-MB and LDH), malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) expression. Additionally, the histopathological analysis of 5-FU revealed dystrophic calcification (DC) in the cardiac tissues and neutrophil infiltration in the lung tissues. However, the administration of OLE reduced lipid profiles, glucose, lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB) levels and inflammation, improved antioxidant capacity, and pathological alterations. It seems that OLE exerts cardio-pulmonary protective effects against 5-FU toxicity through the decrease of oxidative stress and inflammatory cytokines.

关键词： Adaptive immunity   biological DMARD  

摘要： Background: The pathogenesis of rheumatoid arthritis (RA) is predominantly attributed to an autoimmune reaction against citrullinated proteins, coupled with aberrations in T-cell differentiation, which are influenced by a confluence of genetic predispositions and environmental factors. Objectives: To identify increased immune cell subsets in RA patients via comprehensive immune phenotyping, covering T cells, B cells, NK cells, dendritic cells, and monocyte subsets, and to investigate the implications of these cellular anomalies. Methods: We conducted immunophenotyping of RA patients' blood using multi-color flow cytometry and investigated factors contributing to the abnormal cell differentiation in vitro. Results: In a comparative study involving 533 patients diagnosed with RA who had never used b/tsDMARDs and 96 healthy individuals, we observed alterations primarily centered around abnormal T-cell differentiation in the patients with RA, with a marked increase in CD4 + effector memory T cells re-expressing CD45RA (CD4 + TEMRA) cells. To explore the role of these cells in pathogenesis, CD4 + TEMRA (CD4 + CCR7 - CD45RA + ) cells were isolated from peripheral blood for transcriptome analysis. These analyses revealed that CD4 + TEMRA cells exhibited a high expression of cytotoxic molecules and displayed cytotoxic CD4 + cytotoxic T lymphocytes (CD4 + CTL)-like functions (Figure 1). Additionally, they prominently expressed p16, a marker indicative of cellular senescence. Furthermore, analysis of the T-cell receptor (TCR) repertoire of these cells revealed a reduced diversity in the TCRs of CD4 + TEMRA cells compared to both CD4 + naïve T cells and CD4 + memory T cells, across both the α and β chains. This suggests an oligoclonal expansion of CD4 + TEMRA cells. It has been demonstrated that the inclusion of hydrophobic amino acids (such as tryptophan, phenylalanine, and leucine) in the CDR3 region of TCRs in T cells may facilitate the recognition of self-antigens. Consequ

关键词： Autoimmunity   Enterovirus   HLA-I molecules   Immunofluorescence   Immunohistochemistry   Pancreas   Type 1 diabetes  

摘要： Aims/hypothesis Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells. Methods Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, n=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb(+), n=20;AAb(++), n=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, n=41) or only insulin-deficient islets (T1D-IDIs, n=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups. Results Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (p<0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (p<0.001 vs ND). Moreover, VP1(+) cells were detected at higher frequency in donors with HLA-I hyperexpression (p<0.001 vs normal HLA-I). Among VP1(+) donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb(++) and T1D-ICI groups (94.9%, p<0.001 vs ND);this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1(+) compared with VP1(-) donors (45.8% vs 16%, p<0.0

关键词： Cytokines and Chemokines   Remission   Innate immunity