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关键词： Key Words   Indoleamine 2   3-Dioxygenase 1   Anti-inflammation   Peptide nucleic acids   Cell penetration   Antisense oligonucleotides   Normal human keratinocytes  

摘要： Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that plays a pivotal role in immune regulation by metabolizing tryptophan into kynurenine, leading to T cell suppression and promoting immune tolerance. However, persistent activation of IDO1 can lead to prolonged immune stimulation in inflammatory conditions such as skin diseases and chronic inflammation. In this study, we developed modified peptide nucleic acids (PNAs) conjugated with cationic lipid chains to target IDO1 pre-mRNA and evaluated their anti-inflammatory effects in human keratinocytes. The modified PNAs demonstrated enhanced solubility, robust binding affinity, and effective penetration into keratinocytes. Quantitative PCR results showed significant downregulation of IDO1 and pro-inflammatory cytokines such as IL-6, IL-8, and PTGS2 in interferon gamma (IFN gamma)-treated keratinocytes. These findings suggest that cell-penetrating PNAs targeting IDO1 hold potential as a therapeutic approach for inflammatory skin disorders and chronic inflammation.

关键词： Crohn's disease   ulcerative colitis   adalimumab   infliximab  

摘要： Background: This study aimed to evaluate the effect of overweight and obesity at the start of anti-TNF therapy on treatment response and relapse rate in children with inflammatory bowel disease (IBD). Methods: This multicenter, retrospective cohort study included 22 IBD centers in 14 countries. Children diagnosed with IBD in whom antitumor necrosis factor (anti-TNF) was introduced were included;those who were overweight/obese were compared with children who were well/undernourished. Results: Six hundred thirty-seven children (370 [58%] males;mean age 11.5 +/- 3.5 years) were included;140 (22%) were in the overweight/obese group (OG) and 497 (78%) had BMI <= 1 SD (CG). The mean follow-up time was 141 +/- 78 weeks (median 117 weeks). There was no difference in the loss of response (LOR) to anti-TNF between groups throughout the follow-up. However, children in OG had more dose escalations than controls. Male sex and lack of concomitant immunomodulators at the start of anti-TNF were risk factors associated with the LOR. There was no difference in the relapse rate in the first year after anti-TNF introduction;however, at the end of the follow-up, the relapse rate was significantly higher in the OG compared with CG (89 [64%] vs 218 [44%], respectively, P < .001). Univariate and multivariate analysis revealed that being overweight/obese, having UC, or being of male sex were factors associated with a higher risk for relapse. Conclusions: Overweight/obese children with IBD were not at a higher risk of LOR to anti-TNF. Relapse in the first year after anti-TNF was introduced, but risk for relapse was increased at the end of follow-up.

关键词： Lentinan   IL-22   ILC3s   Fucosylation   Macrophages   Barrier function   Ulcerative colitis  

摘要： Ulcerative colitis (UC) involves chronic, complex pathology of the intestinal mucosa. Current treatments are limited in efficacy and associated with adverse effects, highlighting the urgent need for improved therapeutic options. Lentinan (LNT), a polysaccharide drug commonly used in clinical immune modulation therapies, shows potential for UC treatment, though its specific targets and mechanisms remain unclear. In this study, LNT administration effectively mitigated DSS-induced colitis in mice, enhanced mucosal barrier function and antimicrobial defense. Specifically, LNT modulated the balance between tissue-resident and infiltrating macrophages, thereby improving pathogen clearance and enhancing the immunological barrier. Notably, we identified a novel effect of LNT in regulating the macrophage Dectin-1-ILC3 axis to increase IL-22 secretion. This led to the modulation of epithelial O-glycan fucosylation, antimicrobial peptides, and epithelial stem cells, thereby strengthening antimicrobial defenses and the physicochemical barrier. Neutralization with anti-IL-22 antibodies diminished the therapeutic effect of LNT in UC, underscoring the critical role of IL-22 in LNT-mediated treatment. Overall, this study highlights the potential of LNT as a novel therapeutic agent for UC, offering new insights into its molecular mechanisms and clinical application.

关键词： Peritoneal macrophages   M1 and M2 macrophages   Interleukins   Liposomes   IL-2   IL-2R alpha   Apoptosis   Inflammation  

摘要： Inflammatory diseases pose a global challenge due to the critical role of macrophages in their pathogenesis. This study evaluated the effects of cationic liposomes encapsulating IL-2 (LIP-IL-2) on murine peritoneal macrophages (MP) polarized towards M1 and M2 phenotypes. M1 MP (CD86+), which overexpressed IL-2R alpha and CD14 receptors, underwent apoptosis following LIP-IL-2 treatment, whereas M2 MP (CD206+) were unaffected. Furthermore, LIP-IL-2 significantly reduced the secretion of pro-inflammatory cytokines, including IL-6, TNF-alpha, IFN-gamma, and IL-12, exclusively in M1 macrophages. These findings suggest that LIP-IL-2 could serve as a promising therapeutic tool for chronic inflammatory diseases by selectively inducing apoptosis in pro-inflammatory M1 macrophages without affecting M2 ones, opening avenues for targeted therapies in diseases where chronic macrophage-mediated inflammation is a key factor.

关键词： acute rejection   amino acid mismatches   EMMA   Eplet   HLA compatibility   HLA mismatch   HLA serotypes   molecular mismatches   PIRCHE  

摘要： The purpose of this single-center case-control study was to investigate the association between HLA serotype mismatch (MM), compared to other HLA MM modalities, and the occurrence of acute rejection (AR) within the first year after deceased donor kidney transplantation. The study included 198 transplants in 99 pairs of recipients of kidneys from the same donor, where one recipient experienced AR and the other survived the first year without AR. Donors and recipients were typed with NGS for 11 HLA loci at high resolution. HLA MM categories included allele groups, alleles, serotypes, amino acids, EMMA, eplet and PIRCHE-II. Additionally, we investigated Cytomegalovirus LIL peptide (CMV LIL) MM. Recipients with AR presented higher frequencies of pre-transplant HLA-ABDR DSA (20.2% vs. 6.1%, p = 0.005) and CMV LIL MM (24.2% vs. 10.1%, p = 0.01). Univariate and multivariate Cox proportional hazards regression for matched-pair analyses were used to test the association between HLA MM and AR. Univariate analyses indicated significant association with DRB1 ST, HLA-DQB1 AG, HLA-DQB1 AL, EMMA C, EMMA DQB1, Eplet ABC and Eplet DQ MM. Different models were tested in multivariate analyses, all including pre-transplant HLA-ABDR DSA and CMV LIL MM. The models were compared using the Akaike Information Criterion (AIC). The best estimate for AR prediction (AIC = 97.6) was the model that included pre-transplant HLA-ABDR DSA (HR = 11.97;p = 0.003), CMV LIL MM (HR = 367.2;p < 0.001), HLA-DRB1 serotype MM (9.65;p = 0.002) and HLA-DQB1 allele MM (HR = 3.54;p = 0.033). In conclusion, this original report demonstrates an association between the HLA-DRB1 serotype MM and AR, highlighting that serotypes are clinically relevant.

关键词： Fibrosis   IFN alpha   Mortality   Systemic sclerosis   Type I IFN  

关键词： HLA-C*08:296   new allele   NGS   relative  

摘要： HLA-C*08:296 differs from HLA-C*08:02:01:01 by two nucleotide changes, one in an exon and one in an intron.

关键词： L-17 inhibition   Immunomodulation   Personalized therapy   Secukinumab   Type 1 diabetes mellitus  

摘要： We report the case of a 30-year-old male with psoriatic arthritis treated with secukinumab (anti-IL-17A) who developed new-onset type 1 diabetes mellitus (T1DM). During follow-up, a consistent reduction in insulin requirements and glycemic variability was observed in the two weeks following each dose of secukinumab. This suggests a possible immunomodulatory effect of IL-17 inhibition on beta-cell function and glycemic control. To our knowledge, this is the first report describing clinical benefits of secukinumab in the early stages of T1DM, highlighting its potential as a therapeutic tool in modulating autoimmune processes involved in disease progression.

关键词： spondyloarthritis   IBD   TNF  

摘要： Objectives: Gut and joint disease commonly co-occur in SpA. Up to 50% of patients with SpA show signs of subclinical gut inflammation, of which 10% develops IBD. However, the mechanisms underlying this gut-joint axis are still unclear. Here we investigated the hypothesis that restricted expression of a pro-inflammatory cytokine in the intestine may trigger the onset of combined gut and joint inflammation. Methods: Intestinal expression of human TNF (hTNF) was achieved by driving hTNF gene expression using the rat FAPB2 promoter, creating a new animal model, TNFgut mice, that expresses hTNF in the proximal intestinal tract. Intestinal-specific TNFgut mice were examined for pathological changes in the intestine and extra-intestinal tissues by means of histology, reverse transcription PCR (RT-PCR) and flow cytometry, along with 16S sequencing on stools. Results: Local expression of hTNF in the epithelium of the small intestine induces a pro-inflammatory state of the proximal intestinal tract, with epithelial alterations and induction of members of the S100 family, as well as local upregulation of Th17 and Treg, but no obvious signs of dysbiosis. Curiously, TNFgut mice develop sacroiliitis (P <0.05) in addition to small bowel inflammation (P <0.05). However, no signs of peripheral arthritis or enthesitis could be documented. Conclusion: Intestinal expression of hTNF is sufficient to initiate a pro-inflammatory cascade culminating in small bowel inflammation and sacroiliitis. Thus, gut-derived cytokines are sufficient to induce SpA.

关键词： allele   genotype   haplotype   HLA   HLA-DM   HLA-DO   MHC   novel allele  

摘要： HLA-DMA, -DMB, -DOA and -DOB are non-classical HLA Class II genes that play a crucial role in the selection of highly stable HLA Class II/peptide complexes on antigen-presenting cells. Although the genes were initially thought to have a limited diversity with less than 13 alleles per gene documented in the IPD-IMGT/HLA Database in 2022, recent studies suggest a potential impact of certain alleles on the outcome of hematopoietic cell transplantation. To gain a deeper understanding of allelic diversity, we sequenced HLA-DMA, -DMB, -DOA and -DOB of 1880 potential stem cell donors from Germany, Poland, Great Britain and Chile, achieving full-gene resolution. Remarkably, we identified 3968 previously undescribed sequences, including 28 distinct novel proteins. The observed allele frequencies were consistent across all studied populations with one dominating protein for each gene: HLA-DMA*01:01 (> 77%), HLA-DMB*01:01 (> 63%), HLA-DOA*01:01 (> 97%) and HLA-DOB*01:01 (> 77%). Notably, a much higher diversity was observed in full-genomic resolution. Finally, we submitted 51 distinct novel sequences for HLA-DMA, 58 for HLA-DMB, 80 for HLA-DOA and 47 for HLA-DOB to the IPD-IMGT/HLA Database. This comprehensive reference database update will not only simplify future genotyping of HLA-DMA, -DMB, -DOA and -DOB but will hopefully also enhance our understanding of the complex process of peptide selection and loading to the HLA Class II proteins.