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关键词： HIV   IFN-alpha   TNF   dendritic cells   flow cytometry   inflammation   single cell RNA-Seq   tuberculosis  

摘要： BACKGROUND:People living with HIV who have history of cured TB have worse outcomes, including increased all-cause mortality and risk for recurrent TB. We hypothesized that persistent and global immune deficits could contribute to these outcomes in people with history of TB. METHODS:We completed FLEX Cellular Indexing of Transcriptomes and Epitopes by Sequencing of PBMC of people living with HIV with (n=6) or without (n=3) TB history at GHESKIO Centers in Haiti. We subtyped dendritic cells using flow cytometry and quantitated cytokines on an expanded cohort (n=29) to confirm FLEX-CITE-Seq findings. RESULTS:Cell types with statistically significantly differential levels of expression for more than 40 genes all had over-representation of a TNF-mediated pathway. In an expanded cohort of 29 people with HIV, we found a larger percentage of plasmacytoid dendritic cells by flow cytometry and increased plasma IL-6, IL-12p70, IL-15, IL-2, IFN-alpha, and TNF in the TB history group (n=18) compared to people with no history of TB (n=11). DISCUSSION:A proinflammatory milieu and immune cell gene expression changes mediated by TNF persist in people living with HIV even years after TB cure. If the differences are pre-existing risk factors or establish during the natural history of HIV and TB infections is still to be determined.

关键词： CD24+CD38+ B cells   Macrophage   interleukin 10   programmed death-ligand 1   specialized pro-resolving mediators  

摘要： Regulatory B cells (Bregs), specifically the CD24⁺CD38⁺ phenotype, are known for their capacity to reduce inflammation by releasing interleukin 10(IL-10). However, their potential role in regulating inflammation through macrophage differentiation is not well understood. This study investigates how CD24⁺CD38⁺ regulatory B cells modulate the differentiation and function of pro-resolving macrophages through programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) interactions and IL-10 secretion. Human CD24⁺CD38⁺ B cells were isolated from peripheral blood and co-cultured with THP-1-derived macrophages. Recombinant IL-10/PD-L1 and neutralizing antibodies were used to conduct gain and loss-of-function studies. Flow cytometry, quantitative PCR, and mass spectrometry were used to evaluate macrophage polarization, efferocytosis activity, and pro-resolving lipid mediator production. After co-culture, M2 polarization, PD-1 expression, and efferocytosis activity were increased significantly. Inhibition of either IL-10 or PD-L1 pathway reduced M2 macrophage differentiation and functional activity. Co-culture of macrophages with CD24⁺CD38⁺ B cells enhanced the production of pro-resolving lipid mediators, particularly 12-HEPE and RvD5 through IL-10 secretion and PD-L1/PD-1 ligation. These findings reveal a novel mechanism by which human CD24⁺CD38⁺ regulatory B cells promote macrophage-mediated resolution of inflammation through IL-10 secretion and PD-L1/PD-1 ligation. By exploring how these regulatory pathways influence macrophage biology, we ultimately aim to uncover novel therapeutic targets for enhancing inflammation resolution in chronic inflammatory diseases.

关键词： HLA-DQB1*06:528   novel allele   sequencing-based typing  

摘要： HLA-DQB1*06:528 differs from HLA-DQB1*06:09:01:01 by a single non-synonymous nucleotide change in exon 2.

关键词： allele variant   next generation sequencing   novel allele  

摘要： The novel alleles HLA-A*24:643, -A*24:02:01:145, and -A*24:07:05 were identified during routine HLA typing.

摘要： Psoriatic arthritis (PsA) is a progressive, multidomain and interleukin-17 (IL-17)-linked disease that results in substantial quality-of-life deficits. Thereby, we conducted a phase 2 randomized, double-blind, placebo (PBO)-controlled trial of sonelokimab (SLK), a nanobody that binds with a similarly high affinity to IL-17A and IL-17F, inhibiting all dimers. Overall, 207 patients with active PsA were randomized to SLK 120-mg or 60-mg every 4 weeks (Q4W;both with induction (WI)), or to 60-mg Q4W with no induction, PBO or adalimumab (reference arm). The primary endpoint of American College of Rheumatology (ACR) 50 at week 12 was met for SLK 60-mg and 120-mg WI (60-mg WI = 46.3% (19/41;odds ratio (OR) = 3.6;95% confidence interval (CI) = 1.3-9.9;P < 0.05);120-mg WI = 46.5% (20/43;OR = 4.0;95% CI = 1.4-11.3;P < 0.01) versus PBO = 20.0% (8/40)). SLK resulted in significant benefits across the key secondary endpoints of ACR20 (60-mg WI = 78.0% (32/41;P < 0.001) and 120-mg WI = 72.1% (31/43;P = 0.002) versus PBO = 37.5% (15/40)) and Psoriasis Area and Severity Index (PASI) 90 at week 12 (60-mg WI = 76.9% (20/26;P < 0.001) and 120-mg WI = 59.3% (16/27;P = 0.003) versus PBO = 15.4% (4/26)). Robust responses were observed among patients randomized to SLK at week 24 for the high-threshold composite endpoints of ACR70 + PASI 100 (exploratory) and minimal disease activity (secondary), achieved by up to 48% (13/27;120-mg WI) and 61% (25/41;60-mg WI), respectively. SLK was well-tolerated;the most common treatment-emergent adverse events were nasopharyngitis (60 mg = 6.1%;120 mg = 5.2%), upper respiratory tract infection (60 mg = 6.1%;120 mg = 4.1%), injection-site erythema (60 mg = 3.7%;120 mg = 3.1%) and headache (60 mg = 2.4%;120 mg = 4.1%). Four cases of mild to moderate oral candidiasis occurred (60 mg = 2.4%;120 mg = 2.1%). Overall, SLK delivered substantial improvements in the signs and symptoms of PsA across various outcomes and domains.

摘要： The pathogenesis of cancer is complicated, with metabolic reprogramming and angiogenesis as the hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation to epigenetically regulate gene expressions and biological processes in cancer, while the effect on tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we first proved that lactate and histone lactylation facilitated melanoma angiogenesis both in vitro and in vivo. Then, through RNA-sequencing and a series of biochemical assays, we found that lactate promoted the transcription of suppression of tumorigenicity 2 (ST2) in tumor-associated endothelial cells via the enhancement of histone lactylation at its promoter, so that to increase the response of endothelial cells to pro-angiogenic interleukin-33 (IL-33) stimulation. In addition, lactate could also suppress high endothelial venules transition of endothelial cells, which was critical for tumor development. Ultimately, the effect of anti-angiogenic drug synergized with lactate dehydrogenase (LDH) inhibition/ST2 inhibition on melanoma growth was proved in vivo. Taken together, we demonstrated that lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis, which delineated a novel regulatory relationship among lactate, histone lactylation and angiogenesis in cancer, and provided a promising combined therapeutic strategy to target angiogenesis from the perspective of cell metabolism and epigenetics in cancer.

关键词： Psoriasis   Biologic therapy   Genetic risk score   ZMIZ1   TGF-beta   STAT pathway   Drug survival   Pharmacogenetics  

摘要： IntroductionBiologic drug survival in psoriasis is variable. While clinical factors such as obesity and comorbidities contribute to early discontinuation, genetic predictors are less defined. The ZMIZ1/TGF-beta/STAT axis regulates immune-metabolic responses and represents a promising pharmacogenetic *** retrospectively analyzed 875 biologic treatment courses from 312 patients with moderate-to-severe psoriasis (NCT07041112). A pathway-based genetic score was derived from seven single nucleotide polymorphisms (SNPs) in the ZMIZ1/TGF-beta/STAT axis and dichotomized at the median. The primary outcome was time to biologic discontinuation, assessed with Kaplan-Meier curves and Cox proportional hazards models adjusted for demographic, clinical, and inflammatory *** with a high genetic score had significantly longer drug survival (hazard ratio [HR] = 0.74;95% confidence interval [CI]: 0.62-0.89;p = 0.0015), despite elevated baseline tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-15, and leptin. This indicates that genetic background simultaneously conditioned immune-metabolic activation and treatment persistence. Predictive value was strongest for anti-IL12/23 agents (HR = 0.44;95% CI: 0.26-0.75;p = 0.002) and anti-TNF therapies (HR = 0.79;95% CI: 0.62-0.99;p = 0.045), but absent for anti-IL17/IL-23 agents after adjustment. None of the circulating biomarkers independently predicted *** functional genetic score in the ZMIZ1/TGF-beta/STAT pathway independently predicted long-term biologic persistence in psoriasis, particularly with anti-TNF and anti-IL12/23 therapies. Its association with immune-metabolic activation suggests that genetic background shapes both inflammatory status and treatment durability. Incorporating such profiling into predictive algorithms may improve treatment personalization and biologic *** RegistrationTrial Registration NCT07041112.

关键词： Bispecific antibody   PD-L1   IL-8   Cancer immunotherapy   Tumor microenvironment   Triple-negative breast cancer  

摘要： Background Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options. Immune checkpoint inhibitors targeting the programmed death-ligand 1 (PD-L1) pathway show restricted efficacy in TNBC, with response rates of only 5-10% as monotherapy. Interleukin-8 (IL-8/CXCL8) signaling promotes immunosuppression and mediates resistance to anti-PD-L1 therapy, necessitating combination approaches to overcome these limitations. However, the underlying mechanisms of enhanced efficacy from dual pathway targeting require further investigation. Methods We generated humanized mouse models by reconstituting immunodeficient mice with human PBMCs from five donors (n = 5 mice/group). MDA-MB-231 TNBC cells were implanted subcutaneously, and mice were treated with vehicle control, atezolizumab (anti-PD-L1), HuMax-IL8 (anti-IL-8), combination therapy, or a novel bispecific antibody BP2402 targeting both PD-L1 and IL-8. Antitumor activity was assessed alongside single-cell RNA sequencing of tumors and mechanistic analyses including immunofluorescence and Western blot. Results Combination therapy demonstrated significantly enhanced tumor growth inhibition compared to atezolizumab monotherapy in responsive donor models (51.28% vs. 39.13% for donor 3, p < 0.01;44.01% vs. 6.57% for donor 4, p < 0.01). Single-cell RNA sequencing showed higher intratumoral T-cell fractions with combination therapy (donor 3: 80.5% vs. 26.7%;donor 4: 63.6% vs. 13.0% compared to control). BP2402 maintained high binding affinity for both IL-8 (KD = 2.132 nM) and PD-L1 (KD = 1.473 nM), and demonstrated superior antitumor efficacy compared to monotherapies (p < 0.001 vs. vehicle, p < 0.01 vs. individual antibodies). BP2402 treatment significantly reduced CXCL8 and VEGFA expression, suppressed JAK1/STAT1 signaling pathway activation, and upregulated pro-apoptotic proteins including FAS and BAX while effectively modulating T cell exhaustion markers PD-1 and TIM-3. Conclusions These r

关键词： VEO-IBD   IL-10R   phosflow   AlphaFold   HSCT  

摘要： Background Very early onset-inflammatory bowel disease (VEO-IBD) can arise from monogenic defects affecting immune regulation. We report a male child with VEO-IBD caused by a homozygous, loss-of-function IL10RB variant (c.562T>G;p.C188G) that has not been previously reported for this disorder. Case Presentation A male infant of Hispanic descent was admitted to our hospital at the age of 8 months due to intractable colitis, perianal fistulas and growth faltering. Endoscopy at nine months of life revealed pancolitis and gastritis. Despite multiple courses of steroids and use of sulfasalazine, their disease remained active. Standard biologic therapies (infliximab and adalimumab) were trialed in the second year of life without improvement. Given the very early onset and severe phenotype, functional testing by phosflow to evaluate the IL-10 signaling pathway demonstrated the absence of STAT3 phosphorylation in response to IL-10 and follow up genetic testing identified a novel homozygous IL10RB missense variant (c.562T>G;p.C188G). Subsequent protein structure analysis using AlphaFold corroborated this loss-of-function phenotype. The patient's condition was partially controlled with anakinra (IL-1 receptor antagonist) as a bridge therapy. At the age of 3 years, the patient underwent an allogeneic hematopoietic stem cell transplant (HSCT) from an unrelated umbilical cord blood donor;however, they experienced engraftment failure, likely due to persistent hyperinflammation and the choice of cord blood for HSCT. The patient continues to have active disease requiring on-going medical management and supportive care. Conclusion We report a novel, loss-of-function IL10RB variant causing VEO-IBD, thus expanding the genotypic spectrum of this condition. This case highlights the diagnostic and therapeutic challenges of IL-10R deficiency-related VEO-IBD. It also underscores the importance of early recognition of monogenic causes of IBD, use of interim immunomodulatory therapies, and t

关键词： Yinhua Pinggan Granules   intestinal flora   short-chain fatty acids   GPR43   type I interferon  

摘要： Objective Derived from Ma Huang Decoction in the Shang Han Lun, Yinhua Pinggan Granules (YHPG) are used in traditional Chinese medicine for treating influenza. This study highlights the gut microbiota's role in intestinal damage and acute lung injury from influenza virus infection, offering insights into influenza A virus prevention and treatment through the gut-lung *** Using a mouse model disrupted by a four-antibiotic regimen, we assessed survival, weight, lung, and spleen indices post-IAV infection. We evaluated lung and intestinal pathology, viral load, and protein expressions via H&E staining, RT-qPCR, and immunofluorescence. 16S rRNA sequencing and targeted metabolomics were utilized to uncover the impact of YHPG treatment on disrupted gut microbiota and its metabolites after H1N1 *** H&E staining showed severe lung and intestinal damage in IAV-infected mice with disrupted gut microbiota. Immunofluorescence results demonstrated that relative depletion of gut microbiota might exacerbate colonic barrier damage in IAV-infected mice. YHPG restored microbiota diversity, increasing SCFA-producing bacteria, aligning with metabolite changes. Western blot and RT-qPCR showed activation of the GPR43-MAVS-IRF3-IFN-I pathway, linked to SCFA *** YHPG alleviate influenza symptoms, promoting SCFA-producing bacteria and maintaining gut homeostasis. They modulate the GPR43-MAVS-IRF3-IFN-beta pathway, suggesting novel treatment avenues for influenza through gut microbiota modulation.