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关键词： chemokine   IFN   immunoglobin   innate immune response   myocarditis  

摘要： Background and PurposeFulminant myocarditis (FM) is a myocardial inflammatory disease that can result from either viral diseases or autoimmune diseases. In this study, we have determined the treatment effects of immunomodulatory drugs on *** ApproachFM was induced in A/JGpt mice by intraperitoneal administration of coxsackievirus B3, after which immunoglobins were administered daily by intraperitoneal injection. On the seventh day, the cardiac structure and function were determined using echocardiography and cardiac catheterisation. Single-cell RNA sequencing (scRNA-seq) was performed to evaluate CD45+ cells in the *** ResultsImmunoglobin, a typical immunomodulatory drug, dramatically reduced mortality and significantly improved cardiac function in mice with FM. ScRNA-seq revealed that immunoglobin treatment effectively modulated cardiac immune homeostasis, particularly by attenuating overactivated innate immune responses. At the cellular level, immunoglobin predominantly targeted Plac8+ monocytes and S100a8+ neutrophils, suppressing their proinflammatory activities, and enhancing antigen processing and presentation capabilities, thereby amplifying the efficiency and potency of the immune response against the virus. Immunoglobin benefits are mediated by the modulation of multiple signalling pathways, including relevant receptors on immune cells, direction of inflammatory cell chemotaxis, antigen presentation and anti-viral effects. Subsequently, ligand-receptor-mediated cellular interactions manipulated by immunoglobin were further confirmed in *** and ImplicationsImmunoglobin treatment significantly attenuated FM-induced cardiac inflammation and improved cardiac function by inhibiting overactivated innate immune responses.

关键词： MRI   Structure   Neuroanatomy   Late effects   Cancer survivorship   Mouse model   Doxorubicin   Cytokines   Inflammation   Histology  

摘要： Purpose: Doxorubicin (DXR) treatment is linked to cognitive impairments in cancer patients, including pediatric survivors. However, since DXR does not readily cross the blood-brain barrier, systemic mechanisms such as DXRinduced elevations of pro-inflammatory cytokines may be key in mediating neurotoxicity. Using a mouse model of pediatric cancer treatment, we investigated cytokine levels following DXR treatment and evaluated its effects on brain toxicity through genetic knockout. Experimental design: Mice were treated with DXR at a childhood-equivalent age (P17 and P19) and sacrificed at P20 to measure cytokine levels in plasma and brain tissue. IL-6 was significantly elevated in both after DXR treatment. We assessed brain volume alterations using longitudinal in vivo MRI (from P14 to P98) and performed histological analysis to further explore DXR impact on the brain in wildtype and Il-6 knockout mice. Results: DXR treatment caused widespread brain volume reductions. The volume reductions were partially rescued in Il-6 knockout mice treated with DXR, which showed progressive brain volume improvements over time. Additionally, histological analysis revealed an increase in the pro-inflammatory microglial marker CD68 in wildtype mice treated with DXR, a response that was mitigated in Il-6 knockout mice. Conclusions: Our results indicate that IL-6 plays a role in DXR-induced brain toxicity, offering a potential mechanism by which DXR affects the brain despite its limited penetration of the blood-brain barrier. This study also provides evidence that targeting IL-6 may alleviate side effects of chemotherapy associated with structural brain changes, such as cognitive deficits in cancer survivors treated with DXR.

摘要： Rationale: Tumor necrosis factor inhibitors (TNFi) infliximab and adalimumab are commonly used third-line treatments for chronic or refractory sarcoidosis. The utility of monitoring TNFi levels and anti-drug antibody (ADA) formation in sarcoidosis is unclear. This study aimed to identify factors associated with TNFi trough levels and ADA prevalence in real-world sarcoidosis patients. Methods: We included sarcoidosis patients treated with TNFi for >= 3 months at an academic specialty clinic who had trough drug and ADA levels assessed due to suboptimal therapeutic response. Associations between TNFi levels and dosing, patient characteristics, concomitant medications, and presence of ADAs were analyzed by univariate analysis. Results: 90 patients (median age 51 years, 66 % female, 60 % Black) met inclusion criteria (64 infliximab, 26 adalimumab). 66 % of patients were on at least 1 additional anti-sarcoidosis medication. The most common infliximab dose was 5 mg/kg every 6 weeks and adalimumab 40 mg weekly. Mean trough levels were 14.6ug/ml and 13.1ug/ml, respectively. ADAs were more prevalent in those on adalimumab (30.8 % vs 19.0 %). ADA presence was significantly associated with low infliximab (p < 0.001) and adalimumab levels (p < 0.001). For infliximab, concurrent use of second-line medications was associated with reduced prevalence of ADAs (8 % vs 38.9 %, p = 0.013) compared to patients on no additional immunosuppression. Discussion: This is the largest reported cohort assessing TNFi drug and ADA levels in sarcoidosis to date. Prevalence of ADAs was high, particularly against adalimumab. Second-line therapy may reduce ADA formation. Monitoring TNFi drug and ADA levels may aid clinicians in managing patients with a suboptimal response to therapy.

关键词： IL-21   shRNA   CCR2   Melanoma   Immunotherapy  

摘要： Interleukin-21 (IL-21), a pivotal immune molecule, exerts an antitumor effect by regulating immune responses in vivo. Nevertheless, the short half-life of IL-21 protein and the difficulty of intratumoral injection of recombinant proteins for the majority of patients present obstacles. We have engineered an IL-21 gene expression vector and confirmed its ability to stably express IL-21 in tumor tissue, exhibiting a certain anti-melanoma effect. Meanwhile, the chemokine CCL2 (chemokine (C-C motif) ligand 2) promotes tumor progression in various cancers by binding to its receptor CCR2 (C-C Chemokine Receptor Type 2), potentially serving as an important target for tumor therapy. However, whether it can synergistically function with IL-21 in antitumor activity remains uncertain. This comprehensive study employed diverse methodologies to validate the anti-melanoma efficacy of an IL-21 and shRNA-CCR2 co-expression plasmid, administered via attenuated Salmonella. By inhibiting CCR2 and augmenting IL-21 levels, this innovative therapy markedly inhibited tumor growth and extended survival in vivo. Mechanistically, it suppressed melanoma cell proliferation, downregulated migration-associated proteins like MMP2 (Matrix Metallopeptidase 2), c-Myc (cellular myelocytomatosis viral oncogene homolog), and CyclinD1 (Cyclin-dependent kinase 4 regulatory subunit 1), and induced apoptosis. Furthermore, it triggered apoptosis in tumor cells while enhancing the presence and infiltration of symbolscript symbolscript T cells, and NK cells (Natural Killer Cells) within the spleen and the tumor microenvironment. This groundbreaking research introduces a novel combinatorial treatment strategy for melanoma, which is expected to transform clinical management.

关键词： Cytokines   IL-33   Tumor microenvironment   Immunocytes   Inflammation  

摘要： Interleukin-33 (IL-33) belongs to the IL-1 cytokine superfamily and plays a critical role in regulating immune responses and maintaining host homeostasis. IL-33 is essential for driving and enhancing type 2 immune responses and is closely associated with the pathogenesis of various inflammatory diseases, infections, and the progression and metastasis of cancers. This study aimed to provide an overview of the anti-tumor effects of IL-33 by examining its complex immunomodulatory functions within the tumor microenvironment and how it regulates immune cells to mediate these effects. We also provided perspectives on the pleiotropic roles of IL-33 in immunomodulation, its potential use in cancer immunotherapies, and possible adverse effects associated with its therapeutic application. Understanding these mechanisms is crucial for developing more effective IL-33-based diagnostic and therapeutic strategies.

关键词： fulminant type 1 diabetes mellitus   CSAD   HLA haplotype   Graves' disease  

摘要： Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes (T1DM) with an acute onset. There are limited reports on FT1DM in pediatric patients. Here, we report the case of a Japanese female infant with FT1DM, representing the youngest female with FT1DM documented to date. The patient was referred to our hospital at 10 mo of age. Although her laboratory findings met the diagnostic criteria for severe diabetic ketoacidosis, her HbA1c level was not excessively high. Anti-glutamic acid decarboxylase and anti-insulinoma-associated protein-2 antibodies were not detected. Test results for insulin autoantibodies were positive. The glucagon stimulation-loading test revealed a C-peptide level of < 0.6 ng/mL. At 8 yr of age, the patient was diagnosedwith Graves' disease. Human leukocyte antigen typing and analysis of a single-nucleotide polymorphism (rs3782151) in CSAD/lnc-ITGB7-1 revealed that the patient was predisposed to FT1DM owing to these two factors. Her findings at the disease onset fulfilled the diagnostic criteria for FT1DM. Although rare in FT1DM, the patient developed Graves' disease, a complication commonly associated with autoimmune T1DM. Moreover, although her condition at onset and genetic predisposition were consistent with those of FT1DM, her clinical course resembled that of autoimmune T1DM.

关键词： anti-IL-1 treatment   anakinra   canakinumab   child   neonate   CAPS   pregnancy   paternal-maternal exposure  

摘要： Objectives To determine the effect of paternal and maternal anti-IL-1 treatment exposures on pregnancies and neonatal outcomes in *** A single-centre study consecutive adult CAPS patients and their partners was performed between January 2012 and July 2024. All were screened for pregnancies and anti-IL-1 exposure before conception and/or during pregnancy;teratogenic co-therapies resulted in exclusion. Data included patient characteristics, disease activity, anti-IL-1 treatment, pregnancy complications, neonatal outcomes and child health *** Among 112 patients 11 pregnancies were recorded including eight maternal and three paternal anti-IL-1 exposures. All patients had moderate CAPS, 43% had hearing loss. At conception, all patients received canakinumab. Among the eight maternal exposures, six switched to anakinra, one refused the switch and continued canakinumab, and one had to be switched back to canakinumab due to significant local injection reactions. Pregnancy complications included one miscarriage and one preterm birth, both associated with disease activity. Neonatal outcomes were favorable, with a mean gestational age of 37 + 6 weeks and an average birth weight of 3028 g. No congenital malformations were observed. Neonatal complications included one presumed sepsis (culture negative) requiring IV antibiotics and one mild respiratory syncytial virus infection. CAPS was diagnosed in 5 of 11 offspring, all of whom achieved effective disease control early, with no cases of hearing loss or *** In summary, the benefit risk ratio of maternal and paternal anti-IL-1 exposure during conception and pregnancy in our CAPS patients was favourable. CAPS disease activity may have a significant impact on development of pregnancy complications.

关键词： Immune checkpoint   3'UTR polymorphisms   SHLA-G   Haplotypes   COVID-19 genetic predisposition   Saudi Arabia  

摘要： The objective of this study is to investigate the the relationships between HLA-G gene variants and sHLA-G with susceptibility to SARS-CoV-2 infection. In this case-control study, 65 Patients with COVID-19 were and 67 healthy controls were genotyped for their main functional polymorphisms namely, the 14-bp Ins/Del (rs371194629), +3003C/T (rs1707), +3010C/G (rs1710), +3027A/C (rs17179101), +3035C/T (rs17179108), +3142C/G (rs1063320), +3187A/G (rs9380142) and +3196C/G (rs1610696) in the exon 8 of the 3' untranslated regions (3' UTRs) using sanger sequencing method. Associations were assessed for five inheritance models (codominant, dominant, recessive, over-dominant and log-additive). Moreover, the levels of plasma soluble HLA-G (sHLA-G) were explored using ELISA method. Our results revealed that the 14-bp INS/DEL polymorphism was strongly associated with COVID-19 symptoms development for almost all tested inheritance models (p < 0.001). Inversely, the (+3196C/G) polymorphism exhibited a protective effect against COVID-19. In addition, three haplotypes;UTR-1, UTR-3, and UTR-5 were found associated with COVID-19 symptoms (p < 0.05), The level of HLA-G in the serum was significantly higher in COVID-19 individuals than in healthy individuals (p < 0.001).These findings suggest that HLA-G gene polymorphisms in the regulatory 3'UTR region of the HLA-G gene may influence the host immune response to SARS-CoV-2 infection. A deeper comprehension of the functional effect of these associated polymorphisms could be useful in identifying high-risk individuals and in developing adaptive treatments for patients.

关键词： Lung cancer   neutrophils   IL-8   PD-L1   immune escape   tumor microenvironment  

摘要： Background Lung cancer remains a major global health threat due to its complex microenvironment, particularly the role of neutrophils, which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer *** Employing in vitro experimental models, this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-gamma secretion, apoptosis, PD-L1 expression, and T-cell proliferation by using techniques, such as ELISA, flow cytometry, immunofluorescence, and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and *** Lung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils, increased PD-L1 expression, and suppressed T-cell proliferation and IFN-gamma secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS), while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally, CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell *** This study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors, such as IL-8, thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.