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关键词： Paralichthys olivaceus   Interleukin-12   Interleukin-12 receptor subunit beta-2   Th1 cells differentiation   Adjuvant  

摘要： Interleukin-12 (IL-12) regulates the differentiation of CD4+ T lymphocytes into Th1 cells by binding to its receptor, thereby promoting cellular immunity. This study characterized IL-12 and its receptor (32 (IL-12R(32) in flounder (Paralichthys olivaceus) and investigated their interaction, effects on T cell proliferation and differentiation, and the adjuvant effects of IL-12. The recombinant IL-12 was successfully expressed, and the IL-12R(32 antibody was confirmed to specifically recognize IL-12R(32. IL-12 bound to IL-12R(32 at the cellular level. IL-12 stimulation increased leukocyte proliferation and the proportion of CD4+/IL-12R(32+ cells. Moreover, blocking IL-12R(32 with antibody reduced Th1 markers (STAT4, T-bet, IFN-y) and increased Th2 markers (JAK3, STAT6, GATA3). Immunization with rOmpV+IL-12 significantly upregulated CD4+/IFN-y+ cells on day seven, peaked the sIgM+ B lymphocyte response in the fourth week, and enhanced survival after Edwardsiella tarda challenge. In conclusion, IL-12 signaling effectively facilitates the differentiation of Th1 cells and negatively impacts the function of Th2 cells in flounder. This study provides new insights into the immune regulation of CD4+ T cells in teleosts and lays the foundation for understanding the cellular immune mechanisms of vaccines in aquaculture.

关键词： Brazil   HLA   HLA-C   new allele   next-generation sequencing   Rio de Janeiro  

摘要： The novel HLA-C*15:02:01:65Q allele was first described in a potential bone marrow donor from Brazil.

摘要： Background. The development of de novo donor-specific antibodies (dnDSA) and antibody-mediated rejection (AMR) remains a barrier to long-term graft and patient survival. Most dnDSA are directed against mismatched donor HLA-DQ antigens. Here, we describe a novel algorithm, which we have termed categorical amino acid mismatched epitope, to evaluate HLA-DQ mismatches. Methods. In this algorithm, amino acid residues of HLA-DQ protein were categorized into 4 groups based on their chemical characteristics. The likelihood of categorically mismatched peptides presented by the recipient's HLA-DRB1 was expressed as a normalized value, %Rank score. Categorical HLA-DQ mismatches were analyzed in 386 heart transplant recipients who were mismatched with their donors at the HLA-DQB1 locus. Results. We found that the presence of DQB1 mismatches with %Rank score <= 1 was associated with the development of dnDSA (P = 0.002). Furthermore, dnDSA increased the risk of AMR only in recipients who had DQ mismatches with %Rank score <= 1 (hazard ratio = 5.8), but the freedom from AMR was comparable between recipients with dnDSA and those without dnDSA if %Rank scores of DQ mismatching were >1. Conclusions. These results suggest that HLA-DQ mismatches evaluated by the categorical amino acid mismatched epitope algorithm can stratify the risk of development of dnDSA and AMR in heart transplant recipients.

关键词： Anti-TNF   antibody formation   inflammatory bowel disease   loss of response   Saudi Arabia  

摘要： Background: The emergence of tumor necrosis factor inhibitors (anti-TNF) has considerably changed the management of inflammatory bowel disease (IBD) in patients who do not respond to traditional therapies. This study assesses the prevalence of anti-TNF drug levels (DLs) and antibodies (ATAbs) in patients with IBD in Saudi Arabia and explores their associations with IBD type and prior anti-TNF failure. Methods: This cross-sectional study included patients aged 14-75 years diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), treated with anti-TNF medications at King Fahad Medical City over January 2016 to December 2022. Data were analyzed using descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson's Chi-squared test, and multinomial logistic regression. Results: Among 392 patients with IBD (median age, 31 years), 75.8% were diagnosed with CD and 24.2% with UC. Anti-TNF levels were subtherapeutic in 27.0% patients, therapeutic in 21.5%, and supratherapeutic in 51.5%. ATAbs were negative in 73.1% patients, weakly positive in 9.8%, and positive in 17.1%. Subtherapeutic anti-TNF levels were significantly associated with positive ATAbs (P < 0.001). Prior anti-TNF therapy failure was observed in 37.2% cases, with 15.3% showing immunogenicity. No significant demographic differences were noted across ATAbs groups. Conclusion: We highlight the prevalence of subtherapeutic and supratherapeutic anti-TNF levels among patients with IBD in Saudi Arabia and their association with ATAbs. The findings underscore the importance of monitoring anti-TNF DLs and ATAbs to optimize treatment outcomes in IBD management. Future research should focus on the longitudinal impact of these factors and explore genetic predictors of treatment response.

关键词： HLA   HLA-B*58:01:50   novel allele   sequence-based typing   Taiwanese  

摘要： Nucleotide substitution in codon 164 of HLA-B*58:01:01:01 results in the novel allele, HLA-B*58:01:50.

关键词： DC-SIGN   IL-10   anti-inflammatory effects   veterinary autoimmune diseases   veterinary immune-mediated diseases   DC-SIGN ligands   DC-SIGN homologues in animals   comparative medicine   translational research  

摘要： DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) is a C-type lectin receptor expressed on dendritic cells and M2 macrophages, playing a key role in immune regulation and pathogen recognition. Its ability to mediate anti-inflammatory effects by interacting with specific ligands triggers pathways that suppress pro-inflammatory responses and promote tissue repair, making it a potential therapeutic target for inflammatory and autoimmune diseases. DC-SIGN homologs in various animal species share structural similarities and perform comparable immune functions, offering valuable insights into its broader application across species. By recognizing carbohydrate ligands on pathogens, DC-SIGN facilitates immune modulation, which can be harnessed for developing therapies aimed at controlling inflammation. In veterinary medicine, autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, represent significant challenges, and the anti-inflammatory properties of DC-SIGN could provide new therapeutic options to improve disease management and enhance animal health. Future investigations should focus on the structural and functional analysis of DC-SIGN homologs in various species, as well as the development of preclinical models to translate these findings into clinical interventions bridging veterinary and human health.

关键词： "Tuberculosis   Circulating cytokines   Pro-inflammation   Anti-inflammatory  

摘要： Background: In human tuberculosis, Mycobacterium tuberculosis elicits immunopathology characterized by abnormal expression of plasma cytokines. This immunopathology may influence the severity of illness and the efficacy of prolonged anti-mycobacterial treatment. Methods: The study analysed TNF-alpha, IL-10, and TGF-(3 levels in 90 pulmonary tuberculosis patients and compared them with 90 healthy individuals. The tuberculosis patients were categorized as mild, moderate, or advanced based on chest x-ray results, and the ratio of pro-inflammatory to anti-inflammatory cytokines was compared. Results: All three cytokines were present in most tuberculosis patients, and their concentrations were noticeably higher than in healthy individuals. The ratio of TNF-alpha/IL-0 and TNF-alpha/TGF-(3 demonstrated the most powerful discriminatory ability in determining the severity of tuberculosis. The levels of TNF-alpha/IL-0 and TNF-alpha/ TGF-(3 in individuals with moderate and advanced tuberculosis were markedly elevated compared to those with mild cases. The area under the curve (AUC) for TNF-alpha/TGF-(3 and TNF-alpha/IL-0 was determined to be 0.823 and 0.814, respectively. Conclusions: The elevated ratio of TNF-alpha/IL-0 and TNF-alpha/TGF-(3 in the sera of TB patients may contribute to an excessive pro-inflammatory response, whereas a lower ratio may regulate excessive inflammation. Both the TNF-alpha/IL-0 and TNF-alpha/TGF-(3 ratios may effectively categorize the tuberculosis severity and have the potential to serve as biomarkers for evaluating the early response to treatment.

关键词： aspergillosis   Candida spp.   candidemia   cryptococcosis   deep fungal infection   immunodeficiency   pityriasis versicolor   systemic infection  

摘要： TNF-alpha inhibitors, including infliximab, adalimumab and etanercept, are used to treat various inflammatory diseases, such as arthritis, psoriasis and ankylosing spondylitis. However, these treatments may predispose patients to fungal infections, including histoplasmosis, candidiasis and aspergillosis. In this study, we systematically reviewed case reports to critically examine the correlations between anti-TNF-alpha therapies and the occurrence of invasive and superficial fungal infections. Infliximab was the most commonly used TNF-alpha inhibitor (50.65%). The highest number of fungal infections during anti-TNF34 alpha therapy was reported in the USA (84.25%). The conditions treated primarily included rheumatoid arthritis. A total of 517 invasive fungal infections were identified, including histoplasmosis, invasive candidiasis and aspergillosis, with histoplasmosis being the most common. Most studies were conducted in higher-income countries, highlighting the critical lack of research on the use of immunobiologicals in relation to fungal diseases in African countries, which requires further attention. Logistic regression analysis revealed significant associations between adalimumab use and increased risks of candidiasis, coccidioidomycosis, onychomycosis and pityriasis versicolor. For etanercept, significant associations were found with aspergillosis, coccidioidomycosis, cryptococcosis, dermatophytosis, invasive candidiasis, pityriasis versicolor and onychomycosis. Infliximab use was significantly associated with coccidioidomycosis, onychomycosis, aspergillosis, cryptococcosis, histoplasmosis and invasive candidiasis. The data presented in this study clearly demonstrate an association between the use of TNF-alpha inhibitors and an increased risk of fungal infections. It is imperative that healthcare professionals maintain a high level of vigilance when managing patients on these medications. Regular monitoring and proactive management strategies are essential to

关键词： Allergic rhinitis   FABP4   Inflammatory response   Barrier dysfunction   Ferroptosis  

摘要： This study was conducted to investigate the role and the mechanism of fatty acid-binding protein 4 (FABP4) in allergic rhinitis (AR). To induce AR in vitro, human nasal epithelial cells (hNECs) were treated by interleukin (IL)-13. Real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot were used to detect FABP4 expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect the inflammatory level while inflammation-related proteins were detected by western blot. Immunofluorescence (IF) assay was used to detect mucin-5AC (MUC5AC) and zonula occludens-1 (ZO-1) level. The expressions of tight junction proteins were detected by western blot. Lipid reactive oxygen species (ROS) was detected using a BODIPY 581/591 C11 kit and iron level was detected by corresponding assay kits. Ferroptosis-related proteins were detected by western blot. With the goal of investigating the mechanism of FABP4 associated with ferroptosis, cells were pretreated by ferroptosis inducer erastin (30 mM) and rescue experiments were implemented. In this work, FABP4 expression was increased in hNECs treated by IL-13. After FABP4 was knocked down, the inflammation, mucus production, barrier dysfunction and ferroptosis induced by IL-13 in hNECs were all repressed. Nevertheless, erastin pre-treatment partially counteracted the protective role of FABP4 depletion against inflammation, mucus production and barrier dysfunction in IL-13-treated hNECs. In summary, FABP4 deficiency ameliorated IL-13-induced inflammatory response and barrier dysfunction in nasal mucosal epithelial cells through the regulation of ferroptosis.

关键词： breast cancer   ferroptosis   HMGB3   IFN-gamma   immunotherapy  

摘要： Our previous studies showed HMGB3 expression may correlate with immunotherapy efficacy in breast cancer patients. Here, we investigated whether HMGB3 overexpression has an impact on anti-PD-1 therapy in triple-negative breast cancer (TNBC) and its molecular mechanisms. Animal models were established to observe the effect of HMGB3 on sensitivity to anti-PD-1 treatment. Correlation of HMGB3 expression and ferroptosis preventive proteins in TNBC patients' tissues with anti-PD-1 therapy efficacy was analyzed. The impact of HMGB3 on IFN-gamma (Interferon-gamma) inhibitory effects and signaling was examined in human TNBC cells where HMGB3 expression was knocked down using siRNA. Moreover, TNBC cells stably transfected with lentiviral vectors containing cDNA of HMGB3 were also used to confirm the effect of overexpression of HMGB3 on IFN-gamma inhibitory effect and signaling. Effect of HMGB3 on IFN-gamma-driven ferroptosis and ferroptosis-associated protein expression were also investigated. Correlation of HMGB3 and IRF1 and GPX4 expression in patient's cancer tissue were also investigated. Our results demonstrated that HMGB3 expression contributes to resistance to anti-PD-1 therapy in vivo. HMGB3 expression correlated with treatment efficacy of immunotherapy and survival in TNBC patients. HMGB3 silence decreased resistance of breast cancer cells to IFN-gamma cytotoxic effect, while HMGB3 overexpression increased resistance of these cancer cells. HMGB3 silence increased STAT1 phosphorylation and IRF1 expression upon IFN-gamma treatment compared with control. Overexpression of HMGB3 inhibited STAT1 phosphorylation and IFN-gamma signaling in TNBC cells. Moreover, HMGB3 also increased STAT3 activation and had an effect of interaction between STAT1 and STAT3. HMGB3 overexpression decreased IFN-gamma-driven ferroptosis in TNBC cells. HMGB3 increased ferroptosis-inhibitory proteins (SLC7A11, GPX4, and SLC3A2) expression in TNBC cells. Ferroptosis inhibition recovers resistance to