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关键词： Eosinophilia   tumor necrosis factor-alpha inhibitors   etanercept   golimumab   hematologic side effects   biological  

摘要： Introduction We present an unusual case of a 28-year-old rheumatologic male patient who developed eosinophilia while he was on etanercept therapy first and then on *** Representation Although eosinophilia is rarely reported in the literature as a side-effect of various Tumor Necrosis Factor-alpha [TNF-alpha] antagonists, it represents a riddle about the future treatments of these patients since the persistence of therapy might lead to the onset of dermatologic or visceral eosinophilic complications in such *** Furthermore, the pathogenesis of eosinophilia is still unknown, and all the proposed hypotheses do not explain the eosinophilic proliferation in certain subjects.

关键词： Immune mediated inflammatory diseases   Endoplasmic reticulum aminopeptidase   HLA   Single nucleotide polymorphism   Genetics  

摘要： Single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 genes have been associated with susceptibility to various immune-mediated inflammatory diseases (IMIDs). We utilized a unique cohort from the National Centre for Autoimmune Diseases (NCAS) to investigate whether specific SNPs in ERAP1 and ERAP2 act as a shared genetic susceptibility factor across various IMIDs. The study population comprised 171 patients from the NCAS cohort with two or more IMIDs and 57 healthy controls. Using real-time PCR allelic discrimination methods, we genotyped specific SNPs in ERAP1 (rs30187, rs27524), ERAP2 (rs2248374) and HLA-C (rs4406273). The distribution of ERAP1 and ERAP2 risk/minor alleles, genotypes and haplotypes was similar in the NCAS cohort and in healthy controls. When stratifying for HLA-C*06:02 positive psoriasis patients, a disease-associated haplotype A-A-T (rs2248374, rs27524, rs30187) was identified, significantly increasing the odds for having psoriasis and one or more IMIDs (OR = 3.41, 95 % CI: 1.32 - 8.78, p = 0.008). While SNPs in ERAP1 and ERAP2 may not constitute a shared susceptibility factor across all IMIDs, this study suggests a complex interaction between HLA types, ERAP1, and ERAP2, potentially influencing the development of certain MHC-I-associated disorders.

关键词： Obstructive uropathy   Losartan   Zinc oxide nanoparticles   Renal tubulointerstitial damage  

摘要： AimAlthough the relief of ureteral obstruction seems to be a radical treatment for obstructive uropathy (OU), progressive kidney damage is the result because of the associated increased apoptosis and fibrosis. Therefore, it is urgent to find a complementary renoprotective therapy against partially obstructed uropathy cascades. Thus, this study investigated the renoprotective effects of both losartan (LOS) and zinc oxide nanoparticles (ZnONPs) in partial unilateral ureteral obstruction (PUUO). Main methodsIn controlled (n = 16) and shamed (n = 16) study, 64 healthy male Sprague-Dawley rats, both PUUO and right nephrectomy (RNX) were induced. The rats were equally allocated into four groups according to treatment protocol: (1) PUUO group (no treatment), (2) ZnONPs group, (3) LOS group and (4) ZnONPs/LOS group. Antioxidant status and gene expression were assessed in renal tissues. Moreover, histologic and immunohistochemical examinations were performed. Key findingsLOS and ZnONPs significantly mitigated the PUUO-induced renal injury, by significant (P < 0.0001) suppressing of oxidative stress (MDA and TOS), upregulating of antioxidant gene (SOD) and antiapoptotic gene (BCL2), and downregulating the expression of inflammatory cytokines (TNF-alpha, and IL6), apoptotic gene (Bax) and fibrotic marker (beta-Catenin). The combination of both agents offered a more powerful renoprotective effect with additional significant upregulation of the antioxidant marker (TAC, P < 0.0001). SignificanceBoth losartan and ZnONPs and specially their combination have synergistic action in protecting the kidney against PUUO-induced chronic renal cascades through improvement the renal function tests, amelioration of oxidative stress, inhibition of induced apoptosis and fibrosis with marked renal regeneration which highlights the possible application of these drugs as a complementary therapies for different chronic renal degenerative diseases.

关键词： HLA   HLA-DQA1*01:176   new allele   next-generation sequencing  

摘要： The HLA-DQA1*01:176 allele differs from the HLA-DQA1*01:03:01:07 allele by a single nucleotide at codon 175 in exon 3.

关键词： Psoriasis   Bimekizumab   Gender   Treatment   Real world evidence  

摘要： Introduction Several studies have demonstrated that psoriasis severity is generally greater in male patients, but it is unclear whether this gender difference may affect short-term therapeutic response. Notably, no studies have specifically investigated bimekizumab, a humanized, full-length IgG1 monoclonal antibody that acts as a dual inhibitor of interleukin (IL)-17A and IL-17F. Methods This was a cross-sectional, observational, retrospective, multicenter analysis. A cohort of 318 patients with moderate to severe psoriasis, 229 male patients (median [IQR] age 35 [23-67] years) and 89 female patients (median [IQR] age 33 [20-68] years), were retrospectively evaluated for short-term response (16 weeks) to bimekizumab according to standard dosage (320 mg at weeks 0, 4, 8, 12, and 16, and every 8 weeks thereafter). Patients were assessed to evaluate whether gender differences in demographic and clinical characteristics can affect treatment response to standard dose of bimekizumab, during the first 16 weeks of treatment. Therapeutic outcomes were evaluated by analyzing Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores recorded in each patient at three consecutive time points: baseline (T0), after 4 weeks (T4), and after 16 weeks of treatment (T16). Results Male patients showed more severe disease at baseline, compared to female patients (p = 0.01). A significant reduction in disease severity was observed in both male and female patients after 16 weeks of treatment, but male patients showed a faster decrease in PASI score between baseline and week 4 of treatment compared to female patients (p < 0.001). Nevertheless, by week 16, difference in PASI response and DLQI reduction between genders became less pronounced. Conclusion Although male patients exhibit greater disease severity at baseline compared to female patients, this does not result in a differential response to bimekizumab over the short term. Both male and female patients

关键词： Toxoplasma gondii   Macrophages   Messenger RNA   Immune response   Gene expression   Tachyzoites   Inflammation   5' UTR  

摘要： Toxoplasma gondii (T. gondii) is an opportunistic parasite. After infection, macrophages finely regulate the immune response to restrict parasite proliferation. It is well-known that N6-methyladenosine (m6A) plays a critical role in fine-tuning gene expression. To investigate whether m6A modification is involved in regulating the anti-infection immune response in human macrophages against T. gondii, this study utilized T. gondii tachyzoites from the RH strain to infect human THP-1 macrophages. qPCR and ELISA results show that T. gondii infection mounted the expression of TNF-alpha, IL-1 beta, and IL-6. Transcriptomic data suggest that the infection of T. gondii induced differential gene expression in pathways associated with TNF signaling and cytokine-cytokine receptor interaction. Meanwhile, expression of m6A regulators were evaluated using qPCR and Western blotting. T. gondii infection increased the abundance of m6A demethylase FTO and methyltransferase WTAP. Joint analysis of RNA-seq and m6A-seq data was utilized for enriching differentially expressed genes (DEGs) with significantly altered m6A modifications. Intriguingly, following T. gondii infection, the m6A levels of DEGs associated with toxoplasmosis, TNF signaling pathway, and NF-kappa B signaling pathway were significantly different. The m6A-IP-qPCR assay further confirmed that T. gondii infection led to the decrease in the levels of m6A modification in the 3'UTR and 5'UTR regions of TNF-alpha mRNA. Knocking-down of FTO retarded the infection induced-decrease in the levels of m6A modification in TNF-alpha transcripts, accompanied by dampened immune response and uncontrolled T. gondii proliferation. Furthermore, the YTHDF2 RIP assay indicates that T. gondii infection remarkably weakened the binding of YTHDF2 to TNF-alpha mRNA, which could mount TNF-alpha expression by inhibiting the degradation of TNF-alpha mRNA. Overall, these findings suggest that m6A plays a role in the T. gondii infection-induced immune

关键词： HLA   HLA-C*08:01:36   new allele   next-generation sequencing  

摘要： The HLA-C*08:01:36 allele differs from HLA-C*08:01:01:01 allele by a single nucleotide at position 42 G > C in exon 1.

关键词： IL-21 antagonists   marine natural products   molecular docking   molecular dynamics simulation   systemic lupus erythematosus  

摘要： Dysregulated activation of the interleukin-21 (IL-21)/IL-21 receptor (IL-21R) signaling pathway is strongly associated with inflammatory and autoimmune disorders, which positions the pathway as a promising therapeutic target. Given the current lack of approved inhibitors or monoclonal antibodies targeting IL-21/IL-21R, we employed a structure-based virtual screening strategy coupled with experimental validation to identify potential IL-21 antagonists from a library of marine natural products provided by TargetMol. Our investigation identified fucoxanthin, a marine-derived carotenoid, as a potent binder to IL-21R, exhibiting a docking score of -8.19 kcal/mol. Molecular dynamics simulations further confirmed the stability of the IL-21R-fucoxanthin complex, with a calculated binding free energy (Delta G) of -33.25 kcal/mol as determined by MM/PBSA analysis. Importantly, fucoxanthin demonstrated significant immunomodulatory effects by reducing the frequency of key immune cell populations, including CD19+ B cells, memory B cells, and activated follicular helper CD4+ T (Tfh) cells in cultures of peripheral blood mononuclear cells in vitro. These findings suggest that fucoxanthin acts as a potential IL-21 antagonist, offering a novel therapeutic avenue for autoimmune diseases driven by aberrant B- and T-cell differentiation via the IL-21/IL-21R axis.

关键词： Infection   Inflammation   Autoimmunity   Immunogenetics   MHC   TLR   Psychiatric disorder  

摘要： The spectrum of infectious risk organisms showing associations with psychiatric traits is expanding. Infectious agents can modulate the risk of psychiatric disorders at different stages of life, such as gestational, childhood, adolescent, and adult periods. Prenatal infection appears to 'prime' the developing brain, whereas infection during childhood or later periods may act as a 'second hit', and these may have synergistic effects on the risk of developing psychiatric diseases. However, neither all the individuals with antecedent infection develop psychiatric disorders, nor do infectious organisms alone lead to psychiatric phenotypes. This suggests modulatory effects of additional host factors. The host genetic background crucially determines differential susceptibility to infection and serves as an important gateway for immune activation and signalling, as well as homeostatic brain functions. Despite the presence of several immune checkpoints and effectors, the infectious organisms disrupt the balance between immune-activating and immune-compensatory mechanisms and contribute to immune dysregulation. This depends substantially on genetic loci encoding immune molecules such as Toll-like receptors, Major Histocompatibility Complex, cytokines/ chemokines and their receptors, complement proteins, and other molecules and elements such as human endogenous retroviruses and gut microbiome that have distinct roles in immune regulation and immune effector functions. Genetic variations within these loci not only influence differential susceptibility to infection but also confer risk to psychiatric disorders. This article highlights a comprehensive overview of the nexus between infections and immune function-related genes and their impact on psychiatric traits. Understanding such interactions will lead to the identification of genetic markers of susceptibility to infection and psychiatric diseases.