Hans Holm Uhlig

Background: T cells are often enriched at barrier tissues, yet little is known about their roles in barrier sensing and relevance to associated disease. CD1a is a major histocompatibility complex class I-like molecule expressed by Langerhans cells, and forms complexes with lipid antigens to facilitate recognition by nonclassical CD1a-reactive T cells. Objectives: To investigate the role of CD1a in the disease pathogenesis of atopic dermatitis (AD). Methods: Human skin challenge, single-cell and spatial transcriptomic-based approaches and functional immunology were used to assess the role of CD1a in AD pathogenesis. Results: Skin allergen challenge in individuals with AD induced skin CCL17 and CCL22 concentrations that promoted CCR4+ T-cell migration. Single-cell resolution proteo-transcriptomics from human lesional AD skin tissue identified a dominant CCL17/CCL22 source as a persistent population of activated skin CD1a+ dendritic cells (DCs) previously shown to be transiently enriched in human skin wounds. Single-cell resolution spatial tissue analyses showed that these cells were predominantly located within lesional subepidermal microcompartment clusters co-localizing with distinct subpopulations of T helper 2 (Th2) cells. Activated skin DCs expressed neutral sphingomyelinase, which processed inhibitory long-chain sphingomyelin to drive Th2 cell CD1a autoreactivity. Conclusions: The findings are consistent with human CD1a-autoreactive T cells sensing chronic skin barrier compromise through the detection of altered sphingomyelin cycle activity, with implications for the pathogenesis of atopic and related disease.

Background and aims: Evidence-based, mechanism-guided therapies are urgently needed for treating monogenic inflammatory bowel disease (mIBD). For such rare diseases, mechanistic insight is essential to guide treatment when conventional clinical trials are often not feasible. We aimed to summarize literature-based evidence and to identify knowledge gaps. Methods: We conducted a systematic review of published manuscripts evaluating the therapeutic efficacy in mIBD. We quantified and compared the global therapeutic response score across treatments and conditions. In a subset of conditions, biomarkers of longitudinal therapeutic response were evaluated in comparison to non-monogenic pediatric IBD cohorts. Results: Responses to 35 therapeutics across the 102 known genetic causes of mIBD were evaluated in 241 articles and 669 patients, summarizing 302 gene–drug responses. The efficacy of at least one pharmacological intervention was identified in 61% (n = 62/102) of the mIBD conditions, highlighting a major unmet need for effective medications in many others. Gene- and pathway-specific responses were demonstrated for several therapies, including allogeneic hematopoietic stem cell transplantation, gene therapy, and advanced therapies such as anti-TNF agents, IL-1 inhibitors, mTOR inhibitors, as well as eculizumab in CD55 deficiency, abatacept in CTLA4 deficiency, and the immunometabolic agent empagliflozin in glycogen storage disease type 1b. Conclusions: This study highlights the potential of precision medicine approaches tailored to genetic and pathway-specific mechanisms, while underscoring the urgent need for effective therapies in many monogenic conditions that remain without established treatment options.

Background: Interleukin-10 (IL-10) is an essential regulator of intestinal immune homeostasis. Neutralising autoantibodies against IL-10 (anti-IL-10) have been identified in children and also adult patients with IBD. Positivity for anti-IL-10 autoantibodies was associated with carriage of HLA-DRB1*01:03 allele. Objective: To determine the prevalence of anti-IL-10 in paediatric IBD and assess the associated clinical phenotype. Design: We conducted a cross-sectional multicentre study across paediatric IBD cohorts from four countries. Anti-IL-10 antibodies were investigated in serum and plasma from paediatric patients with IBD (mean age of IBD onset 11.2±3.8 years). IL-10-neutralisation capacity was confirmed by functional IL-10 reporter assay, competitive ELISA and cytokine release assay. Clinical data were analysed to evaluate disease phenotype and treatment outcomes, with comparison with matched controls. HLA-DRB1*01:03 analysis was performed. Results: Anti-IL-10 positivity was identified in 26/1045 paediatric patients with IBD (2.5%) (Crohn’s disease n=6, UC n=19, IBD unclassified n=1; IBD diagnosis age of 13±3 years). Anti-IL-10 autoantibodies were of the IgG class and amplified pro-inflammatory cytokine responses in vitro. Anti-IL-10-positive patients exhibited more severe disease compared with matched controls, including an increased prevalence of difficult-to-treat disease (23% vs 6%, p=0.03), higher rate of acute severe UC (26% vs 6%; p=0.038) and higher rates of colectomy (27% vs 6%, p=0.01). Eighty percent (16/20) of anti-IL-10-positive patients with available HLA data carried the HLA-DRB1*01:03 allele, compared with 1.5% in the anti-IL-10-negative group. Conclusion: Anti-IL-10 autoantibodies are present in a subgroup of paediatric patients with IBD and are associated with difficult-to-treat disease.

Prunotto et al. describe clinical presentation, immunological status, treatment, and long-term outcomes of a large cohort of pediatric and adult patients affected by an extremely complex and rare immunodeficiency known as TTC7A deficiency for which no clear therapeutic pathway is currently available.

Inflammatory bowel disease (IBD) is a polygenic condition, influenced by environmental factors, and demonstrating marked phenotypic heterogeneity. While genetic susceptibility is well characterised, genetic determinants of disease severity and progression remain unclear. We report the novel divergent effects of HLA-DQA1:p.Gln198Glu , associated with increased risk of complicated Crohn’s disease (odds ratio [OR]=1.15, P=2.41x10-9) and reduced severity in ulcerative colitis (OR=0.81, P=8.98x10 ^-12 ), particularly reduced risk for colectomy (OR=0.69, P=6.74x10 ^-12 ).

Childhood mortality remains high in low-resource settings, where environmental enteric dysfunction (EED) is prevalent. Peripheral blood bacterial lipopolysaccharides (LPS) are potential biomarkers of intestinal microbial translocation and inflammation; however, the effects of LPS translocation on mortality in this context remains unexplored. We investigate the association between plasma LPS and mortality among 638 acutely ill hospitalised children and compare them to 251 well community peers in a nested case-cohort (NCC) conducted between November 2016 and January 2019 across 9 sites in 6 countries in sub-Saharan Africa and South Asia. Higher levels of plasma LPS and inflammatory biomarkers (fecal calprotectin, plasma myeloperoxidase, and CD14) are associated with elevated 90-day mortality, and those associations are independent of wasting status. Non-survivors with high plasma LPS exhibit elevated gram-negative enteric microbiota, increased fecal biomarkers of EED, systemic inflammatory proteins, and differentially expressed proteins linked to the Insulin-like growth factor (IGF) nutritional axis, Interleukin-1 and collagen regeneration. Cellular interaction network models deconvoluted from a single-cell transcriptomic dataset enable an exploratory investigation of systemic immune responses and epithelial-immune cells crosstalk active in pathways leading to mortality. This knowledge can guide the identification of potential therapeutic signaling pathways in settings with high EED and malnutrition.

The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4⁺ T cells, intraepithelial lymphocytes, CD8⁺ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions. Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.

Background: There are scarce data available on upadacitinib in children with Crohn's disease (CD).Aim: To evaluate the effectiveness and safety of upadacitinib as an induction therapy in paediatric CD.Methods: This was a multicentre retrospective study between 2022 and 2024 of children treated with upadacitinib for induction of remission of active CD conducted in 30 centres worldwide affiliated with the IBD Interest and Porto group of the ESPGHAN. We recorded demographic, clinical and laboratory data and adverse events (AEs) at week 8 post‐induction. The analysis of the primary outcome was based upon the intention‐to‐treat (ITT) principle.Results: We included 100 children (median age 15.8 [interquartile range 14.3–17.2]). All were previously treated with biologic therapies including 89 with ≥ 2 biologics. At the end of the 8‐week induction period, we observed clinical response, clinical remission and corticosteroid‐ and exclusive enteral nutrition‐free clinical remission (CFR) in 75%, 56% and 52%, respectively. By the end of induction, 68% had achieved normalisation of C‐reactive protein, and 58% had faecal calprotectin (FC) < 150 mcg/g. There was combined CFR and FC remission in 13/31 children with available data at 8 weeks (13% of the ITT population). AEs were recorded in 24 children; the most frequent was acne in 12. Two AEs (severe acne and hypertriglyceridemia) led to discontinuation of therapy.Conclusion: Upadacitinib is an effective induction therapy for refractory paediatric CD. Efficacy should be weighed against the potential risks of AEs.