Citations

ABSTRACT Background and Aims Autoimmune hepatitis is an immune‐mediated liver disease characterized by chronic inflammation and progressive fibrosis. Tissue‐resident memory T cells mediate organ‐specific immunity, but their role in autoimmune hepatitis remains poorly understood. We characterized tissue‐residency‐associated T‐cell populations and their cytokine profiles, assessed associations with disease severity and determined whether these signatures were reflected in peripheral blood. Methods Paired blood and liver samples were obtained from 19 patients with autoimmune hepatitis. Comparator cohorts included 20 patients with metabolic dysfunction‐associated steatotic liver disease and 20 surgical patients providing non‐inflamed adjacent non‐tumorous liver tissue. Multiparameter flow cytometry assessed tissue‐residency markers, T‐cell differentiation and cytokine production after polyclonal stimulation. Immune phenotypes were correlated with histological and clinical parameters. Results Autoimmune hepatitis was associated with compartment‐specific remodelling of T‐cell differentiation states and intrahepatic enrichment of CD8 + T cells expressing CD69, CD103 and CXCR6 relative to paired blood and comparator liver tissues. Intrahepatic CD8 + T cells exhibited an interferon‐γ‐dominant cytokine profile, whereas CD4 + T cells showed broader interferon‐γ‐, interleukin‐17A‐ and interleukin‐4‐associated responses. Despite the enrichment of tissue‐residency‐associated CD8 + T cells, cytokine‐producing CD8 + T‐cell populations with and without a tissue‐resident memory phenotype contributed comparably to the hepatic T‐cell compartment. Tissue‐residency‐associated phenotypes correlated positively with Ishak fibrosis stage, whereas the frequency of interferon‐γ‐positive intrahepatic CD8 + T cells correlated inversely with fibrosis. Conclusions Autoimmune hepatitis was characterized by intrahepatic accumulation of phenotypically distinct and functionally active CD8 + tissue‐resident memory T cells associated with fibrosis. This immune profile was not reflected in paired blood, indicating compartmentalized hepatic immune remodelling.

Cholera toxin (CTx) is a potent enterotoxin and widely used mucosal adjuvant, yet the acute host response to CTx itself, in the absence of a co-administered antigen, remains vague. In this study, we integrated physiological and metabolic phenotyping with intestinal transcriptomics, epithelial imaging, immune profiling, hepatic gene-expression analysis, and paired microbiome profiling to characterize the response to a single oral CTx exposure in mice. Within 24 h, CTx remodeled immune-cell composition in both epithelial and lamina propria compartments, with responses shaped by sex and genetic background. Recurrent changes included increased epithelial group 3 innate lymphoid cells, reduced lamina propria RORγt+ regulatory T cells, and decreased epithelial ILC1/NK cells in males of both strains. CTx also increased villus DCLK1+ tuft cells and reduced MUC2 immunoreactivity. Jejunal transcriptomics revealed induction of inflammatory defense, glycolytic, autophagy, and lipid-utilization programs together with suppression of proliferative and mitochondrial programs, consistent with coordinated stress adaptation. These local changes were accompanied by rapid restructuring of the fecal microbial community and by systemic hypometabolism, despite markedly different hypothermic responses across strains. CTx also elicited a selective hepatic stress and metabolic program, including conserved suppression of Cyp7a1 across sexes and strains. Together, these findings show that CTx alone rapidly reorganizes the intestinal immune, epithelial, metabolic, and microbial environment while suppressing whole-body metabolism. This work provides an integrated framework for understanding the acute host response to CTx and for interpreting its widespread use as a mucosal adjuvant.

Objective To characterize regional brain atrophy patterns, evaluate their association with regional leucine‐rich glioma‐inactivated‐1 ( LGI1 ) gene expression, and identify clinical predictors of hippocampal atrophy in LGI1 autoimmune encephalitis (AE). Methods This study compared regional brain volumes in LGI1‐AE patients versus age‐ and sex‐matched healthy controls (HC) and Alzheimer's disease (AD) patients. LGI1 gene expression was derived from the Allen Human Brain Atlas. Multivariable linear regression and generalized linear models were utilized. Results A total of 55 LGI1‐AE patients were included. Median age was 68 years (IQR 62.5–74.2 years) at volumetric analysis, after 19 months (IQR 11–45 months) from symptom onset. Compared with HC ( n = 55) and AD patients ( n = 55), LGI1‐AE patients had greater regional atrophy of the hippocampus, insula, caudate, and putamen ( p < 0.002). Longitudinal analyses demonstrated hippocampal and pallidal atrophy after covariate adjustment. Among those who did not fulfill limbic encephalitis criteria and/or had non‐lesional magnetic resonance imaging, limbic and striatal atrophy were identified compared with HC ( p < 0.01). Regions with the greatest differential atrophy corresponded to higher LGI1 gene expression (Spearman ρ = 0.7, p = 0.005). Severe cognitive deficits at diagnosis ( β = −0.56; p = 0.002) and longer disease duration ( β = −0.01; p = 0.001) independently predicted total hippocampal volume ( R 2 = 0.31). Interpretation LGI1‐AE demonstrates a distinct pattern of limbic and striatal atrophy that differs from AD and aligns with regional LGI1 expression, supporting a model of selective network vulnerability. Greater baseline cognitive impairment and longer disease duration independently associated with hippocampal atrophy, underscoring the potential importance of early diagnosis and treatment to limit structural brain injury. ANN NEUROL 2026

CD4 + effector T helper 1 (T H 1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed T H 1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing T H 1 cell–associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA–dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced T H 1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn’s disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4 + T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell–transfer mouse model of colitis. Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains T H 1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.

Background: This qualitative study sought to understand factors related to low rates of screening mammography among transgender and gender-diverse (TGD) individuals and how these rates might be improved. Methods: Individuals who self-reported as TGD were recruited from multiple sites and national patient advocates. Consenting participants completed an individual interview using a semistructured guide informed by the Health Belief Model (HBM). Interview data were analyzed using thematic analysis. Results: A total of 44 individuals completed the interview (median age, 44.9 years; range, 19–77 years); 11% were a racial/ethnic minority; and 52%, 20%, and 25%, respectively, self-identified as a transgender woman, transgender man, or nonbinary. Three themes emerged around constructs in the HBM. First, individuals voiced a hope to be treated equally (“I just want to go to work, pay my taxes, love my family, and go along my day and be a good human”) and described how such equitable treatment during screening guarded against gender dysphoria and favored gender affirmation (“it is affirming…being treated as any other woman”). Second, barriers and facilitators related to mammography were identified, including the need to address cost/low cost (“screenings are a luxury”); prior negative/positive experiences (“they would call my name and look at me but dismiss me”); absence/presence of education (“none of the doctors…ever told me what that process looks like”); and perceived low/high cancer risk (“my mom died pretty young from breast cancer”). Finally, practical recommendations were offered, including individual changing/waiting rooms, hiring gender-diverse staff, and engaging clinicians who provide whole-person, trauma-informed care. Conclusions: Mammographic screening among TGD individuals could be improved by proactively creating safe, affirming spaces; working to lower costs; providing educational materials tailored to the TGD community about cancer risk and the practical aspects of screening; and hiring gender-diverse staff. These recommendations from TGD participants merit implementation as well as further study.

Abstract Introduction: Otolaryngology trainees must master complex three-dimensional (3D) head and neck anatomy for safe surgical practice. Existing educational resources, including cadaveric dissection and 3D-printed models, are limited by cost and accessibility. Virtual reality (VR) has demonstrated efficacy for anatomy education, yet no published immersive VR module addresses the facial nerve and parotid gland, which are structures critical to otolaryngology training. We describe the design and development of a multimodal VR anatomy module targeting this gap. Methods CTA DICOM data were segmented in Mimics 23.0 and sculpted in ZBrush to generate high-fidelity 3D models. Models were optimized for the Meta Quest 3 standalone headset using the Unity game engine. A reusable, step-based architecture organized content into sequential, otolaryngologist-scripted narrated scenes featuring progressive anatomical disclosure and dynamic highlighting. Multimodal features include CT/MRI slice viewers, parotidectomy surgical video, and 2D anatomical diagrams. Development involved iterative build cycles, followed by informal usability testing with surgeons, residents, and medical students. Results The final module incorporated 65 anatomical structures, achieving a 96.4% polygon reduction (22.7 million to approximately 806,000 polygons) while preserving clinical fidelity. Most users navigated the environment independently. Feedback identified refinement needs including orientation aids, automated narrator pronunciation corrections, and expanded interaction capabilities. Conclusions This proof-of-concept demonstrates that optimized 3D models derived from clinical imaging can be successfully integrated with standalone educational assets in an immersive VR environment. This module addresses a key gap in otolaryngology education and provides a reusable technical and pedagogical framework adaptable to multiple anatomical regions and learner populations.