Higher Promoter Methylation of the Ubiquitin-Associated and SH3 Domain Containing A (UBASH3A) Gene Is Associated With T-Lymphocyte Ontogeny and Reduced Susceptibility to Early-Onset Sepsis Ziyi Wang, Nelly Amenyogbe, Rym Ben-Othman, Bing Cai, Mandy Lo, et al. Journal of Infectious Diseases, 2026 We investigated the genetic and epigenetic regulation of the UBASH3A gene and its association with early-onset sepsis. Using matched whole blood DNA methylation, gene expression, genotypes, and immune cell counts from the EPIC-HIPC newborn cohort, we report that promoter methylation was negatively correlated (Pearson r = −0.5, P < 2.2 × 10−16) with ontogenetic changes in UBASH3A gene expression and circulating CD3+ T-cell numbers. Higher promoter methylation at birth was associated with lower UBASH3A expression and reduced early-onset sepsis risk (odds ratio, 0.26; P = .015). Genetic variation significantly influenced variations in baseline UBASH3A methylation (132 cis-meQTL, false discovery rate <0.05).
Innate Lymphoid Cell Phenotypic and Functional Alterations in Patients With Systemic Juvenile Idiopathic Arthritis Linda Quatrini, Cecilia Ciancaglini, Ivan Caiello, Silvia Santopolo, Manuela Pardeo, et al. Arthritis and Rheumatology, 2025 ObjectiveSystemic juvenile idiopathic arthritis (sJIA) is a chronic childhood disease classically attributed to innate immune cell dysregulation. This study aimed to elucidate the role of innate lymphoid cells (ILCs), including natural killer (NK) cells and helper‐ILCs (hILCs), in sJIA during clinically inactive disease (CID) through phenotypic and functional analysis.MethodsPeripheral ILCs from children with sJIA during CID receiving interleukin‐1 (IL‐1) inhibitors (n = 40) were analyzed by flow cytometry and compared to 23 healthy children (HC) and 22 patients with unrelated autoinflammatory diseases taking IL‐1 inhibitors. Plasma proteomic profiling was also performed.ResultsPatients with sJIA showed a significant reduction in circulating NK cell frequencies compared to HC, with an increased proportion of CD56bright NK cells. Although overall hILC frequencies were comparable to HC, ILC1s were increased, whereas ILC precursors were reduced. ILC1 frequency correlated positively with IL‐18 plasma levels, whereas ILC2 frequency correlated negatively. Functional assessments revealed that NK cells from patients with sJIA had variable interferon γ (IFNγ) production upon IL‐18/IL‐12 stimulation, inversely correlating with IL‐18 levels. Additionally, hILCs from these patients showed a specific impairment in IFNγ production despite normal IL‐13 production, potentially linked to decreased IL‐18 receptor α expression in ILC1s. Proteomic analysis confirmed IL‐18 as the most up‐regulated cytokine in sJIA plasma.ConclusionPatients with sJIA in CID exhibit significant innate immune abnormalities, including altered ILC subset distribution and impaired IFNγ production, strongly associated with IL‐18 levels. These findings suggest ongoing immune dysregulation despite clinical remission, underscoring a potential role for ILCs and cytokine interaction in sJIA pathogenesis.
