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关键词： 1,25D   1,25-dihydroxyvitamin D   1   a   D   1   a   -hydroxyvitamin D (alfacalcidol)   25D   25-hydroxyvitamin D   AIRE   autoimmune regulator   AMP   antimicrobial peptide   APC   antigen-presenting cell   ARI   acute respiratory tract infection   ASL   airway surface liquid   CAMP/LL3   7 cathelicidin antimicrobial peptide   CD   Crohn’s disease   CKD   chronic kidney disease   DBP   vitamin D binding protein   DC   dendritic cell   EAE   experimental autoimmune encephalomyelitis   EB1089   eocalcitol   E.coli   Escherichia coli   HBD2   human   β   -defensin 2   HDACi   histone deacetylase inhibitor   IBD   inflammatory bowel disease   ICI   immune checkpoint inhibitor   IFN   g   interferon-gamma   Ig   immunoglobulin   IIH   infantile idiopathic hypercalcemia   IL   interleukin   iNKT   invariant natural killer T cell   irAE   immune-related adverse effect   KO   knockout   LIC   innate lymphoid cell   LPS   lipopolysaccharide   LXR   liver X receptor   MHC   major histocompatibility complex   MS   multiple sclerosis   mTEC   medullary thymic epithelial cell   NF   κ   B   nuclear factor kappa B   NK   natural killer cell   NOD   nonobese diabetic   OCT   22-oxacalcitriol (maxacalcito)   PBMC   peripheral blood mononuclear cell   PD-1   programmed-death protein 1   PPAR   peroxisomal proliferator-activated receptor   PTH   parathyroid hormone   PRR   pattern recognition receptor   RAG   recombinase activating gene   RAR   retinoic acid receptor   RCT   randomized, double-blind, placebo-controlled trial   RXR   retinoid X receptor   T1D   type 1 diabetes   TB   tuberculosis   TCR   T cell receptor   TEC   thymic epithelial cell   TGF   b   transforming growth factor beta   Tfh   follicular helper T cell   TLR   toll-like receptor   TR   thyroid hormone receptor   Treg   regulatory T cell   UTI   urinary tract infections   UVB   ultraviolet B   VDR   vitamin D receptor   VDRE   vitamin D response element   WT   wild-type  

摘要： Vitamin D was discovered as the cure for nutritional rickets, a disease of bone growth arising from inadequate intestinal calcium absorption, and for much of the 20th century, it was studied for its critical role in calcium homeostasis. However, we now recognize that the vitamin D receptor and vitamin D metabolic enzymes are expressed in numerous tissues unrelated to calcium homeostasis. Notably, vitamin D signaling can induce cellular differentiation and cell cycle arrest. Moreover, the vitamin D receptor and the enzyme CYP27B1, which produces the hormonal form of vitamin D, 1,25dihydroxyvitamin D (1,25D), are expressed throughout the immune system. In addition, CYP27B1 expression in immune cells is regulated by physiological inputs independent of those controlling its expression in calcium homeostatic tissues. These observations have driven the development of 1,25D- like secosteroidal analogs and nonsecosteroidal analogs to separate the effects of vitamin D on cell differentiation and function from its calcemic activities. Notably, some of these analogs have had considerable success in the clinic in the treatment of inflammatory and immune-related disorders. In this review, we described in detail the mechanisms of vitamin D signaling and the physiological signals controlling 1,25D synthesis and catabolism, with a focus on the immune system. We also surveyed the effects of 1,25D and its analogs on the regulation of immune system function and their implications for human immune-related disorders. Finally, we described the potential of vitamin D analogs as anticancer therapeutics, in particular, their use as adjuncts to cancer immunotherapy. Significance Statement: Vitamin D signaling is active in both the innate and adaptive arms of the immune system. Numerous vitamin D analogs, developed primarily to minimize the dose-limiting hypercalcemia of the active form of vitamin D, have been used widely in preclinical and clinical studies of immune system regulation. This r

关键词： CAR Treg   IL23R   Crohn's disease   cell therapy   IBD  

摘要： Background and Aims Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn's disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active *** Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD *** Our study showed that IL23R-CAR displayed negligible tonic signaling and a strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR *** Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD. Graphical Abstract

关键词： chimerism testing   haematological malignancies   peripheral blast   somatic alterations  

摘要： Tumour cells, which are often found in the peripheral blood of patients with acute leukaemia, may harbour multiple somatic alterations throughout the genome, including changes in the HLA region and short tandem repeat (STR) regions. We investigated whether such somatic alterations interfere with HLA and chimerism diagnostics conducted in preparation for an allogeneic haematopoietic stem cell transplantation (allo-HSCT). This study describes 10 patient-based cases for which laboratory diagnostics were performed prior to a possible stem cell transplant in the Maastricht University Medical Center. In three acute leukaemia patients, somatic alterations were detected within the HLA region in peripheral blood samples: one case showed a complete loss of an HLA haplotype, while two cases exhibited somatic mutations affecting a single HLA class I gene. Additionally, seven patients with haematological malignancies revealed somatic variations within the STR regions, indicated by the presence of a third allele or the partial or complete loss of an allele in pre-transplant peripheral blood samples. In all patients, these somatic variations were confirmed by repeating the tests using buccal swab samples from patients or samples from family members. Furthermore, our study demonstrated that somatic alterations within STR regions used for chimerism testing occurred in 6% of the 176 patients who received an allo-HSCT between 2017 and 2022. This study underscores the clinical relevance of detecting somatic alterations prior to allo-HSCT, as they may interfere with HLA and STR analysis, potentially leading to HLA mistyping or incorrect chimerism detection. Additionally, it highlights the frequency with which genetic changes in tumour cells can affect chimerism diagnostics. The findings emphasise the vital importance of selecting the appropriate sample source for typing purposes and considering the patient's karyotype when choosing STRs, especially when tumour cells are present in the p

摘要： Nuclear factor-kappa B (NF-kappa B)/p65, a vital signaling molecule in the NF-kappa B pathway, participates in diverse physiological functions and host-virus interactions. However, the involvement of NF-kappa B/p65 in fish virus infection remains poorly understood. In this study, we explored the role of the p65 in virus infection and its impact on IL- 18 regulation in largemouth bass ( Micropterus salmoides). Bioinformatics analysis showed that the ORF sequence of Msp65 spanned 1941 bp, encoding 646 amino acids with two conserved functional domains, including RHD and IPT domain. Msp65 mRNA was presented in various tissues, with higher levels detected in the liver and gill. After exposure to largemouth bass virus (LMBV), red grouper nervous necrosis virus, lipopolysaccharide and poly (I:C), Msp65 expression was activated in vivo. In addition, the antiviral role of Msp65 were explored. In vitro, Msp65 overexpression hindered LMBV replication and formation of viral assembly site. In vivo, we found that disruption of Msp65 by using maslinic acid (MA) notably promoted the infectivity of LMBV, indicating its antiviral capabilities in largemouth bass. Besides, the downregulation of Msp65 suppressed the expression of inflammatory and interferon signaling molecules. Conversely, Msp65 overexpression boosted the activities of IFN-I, IFN-III and ISRE promoters, suggesting the positive regulation of Msp65 on interferon immune pathway. Furthermore, to unveil the regulatory role of Msp65 on MsIL-18, a promoter investigation was conducted. The luciferase reporter assay demonstrated that Msp65 positively influenced the expression of MsIL18. Subsequent analysis suggested that the putative binding sites for MsIL-18 could potentially reside within the-228 to-203 bp of the MsIL-18 promoter. These findings illustrated that Msp65 involved in LMBV infection by modulating immune responses, presenting a novel insight into the antiviral mechanisms of p65 in bony fish.

关键词： Breast cancer   HLA-A   HLA-B/C   PD-1   PD-L1   prognosticator   survival  

摘要： Background/Aim: Class 1 human leukocyte antigen (HLA) ensures that cytotoxic T lymphocytes (CTLs) attack tumor cells. As part of tumor de-differentiation, the expression of HLA on the tumor cell surface may decrease, which can facilitate tumor growth. Therefore, reduced expression of HLA is generally negatively associated with overall survival (OS). The reverse is true for programmed cell death protein (PD-1) and programmed death ligand 1 (PD-L1). The presence of PD-1 and PD-L1 on the surface of cancer cells inhibits immune defense mechanisms against cancer cells. Therefore, one would expect that increased PD-1/PDL-1 expression would result in decreased 5-year survival. The aim of this study was to correlate the expression levels of HLA-A and HLA-B/C with the expression levels of PD-1 and PDL-1 to evaluate the reliability of their prediction of 5-year OS. Materials and Methods: This study retrospectively examined patients upon the start of a new therapy line for metastatic breast cancer (MBC). The pilot cohort fulfilling very demanding inclusion criteria consisted of 34 patients. The diagnostics were primarily carried out using RT-qPCR.

关键词： HLA   HLA-C   new allele   sequencing-based typing  

摘要： The new allele HLA-C*07:1130N differs from HLA-C*07:02:01:01 by one nonsense nucleotide substitution in exon 3.

关键词： ADRA (amino acid derivative reactivity assay)   BR (borderline range)   EpiSensA (epidermal sensitization assay)   IL-8 Luc (interleukin-8 reporter gene assay)   MAD (median absolute deviation)   MADp (pooled median absolute deviation)   NAC (N-(2-(1-naphthyl)acetyl)-L-cysteine)   NAL (alpha-N-(2-(1-naphthyl)acetyl)-L-lysine)  

摘要： Most predictive models that use alternatives to animal experiments divide judgements into two classes with a cutoff value for each model. However, if the results of alternative methods are close to the cutoff values, the true result may be ambiguous because of variability in the data. Therefore, the OECD GL497 uses a judgement method that establishes a borderline range (BR) around a cutoff value using a statistical method. However, because there is no detailed description of how the BR is calculated, we clarified two specific points. The scale-constant correction method was used to calculate the median absolute deviation (MAD) around the median. In addition, the bottom-raised transformation method was used when the data were "0" because calculation of the BR requires that all data are logarithmic. Indeed, the BRs for the amino acid derivative reactivity assay (ADRA), interleukin-8 reporter gene assay (IL-8 Luc), and epidermal sensitization assay (EpiSensA) were calculated using data from each validation study. The results showed that the BR for ADRA and IL-8 Luc ranged from 4.1 to 5.9 and 1.25 to 1.57, respectively. Furthermore, the BRs of four genes (ATF3, GCLM, DNAJB4, and IL-8) evaluated using EpiSensA ranged from 10.71 to 21.02, 1.64 to 2.45, 1.61 to 2.52, and 3.11 to 5.16, respectively. The difference (deviation) between the lower and upper BR limits and cutoff value for each alternative method were comparable to those of the alternative methods listed in the guidelines (DPRA, KerarinoSens, and h-CLAT) and thus were considered as adequate.

关键词： HLA-DQB1*05:01:01:37 novel allele   Illumina   next-generation sequencing  

摘要： The HLA-DQB1*05:01:01:37 allele differs from HLA-DQB1*05:01:01:02 by a single nucleotide substitution in intron 2.

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.