Biology subjects

Melia, J. M.

Publications and source records attributed to Melia, J. M..

4 recordsLinked to original sources

bioRxiv2025

Longitudinal T cell repertoire analysis reveals dynamic clonal T cell populations in Ulcerative Colitis

BackgroundUlcerative Colitis (UC) is characterized by chronic, relapsing and remitting inflammation in the colon and rectum. Pathogenic T cell activity is thought to play a major role in this process. T cell effector function is determined by the T cell receptor (TCR) and the antigen it recognizes. Examining the TCR repertoire can provide key insights into the adaptive immune response. ObjectiveTo characterize the longitudinal TCR repertoire of patients with UC across disease activity to determine if recurrent antigen(s) are responsible for active inflammation. DesignBulk TCR V{beta} sequencing was done on colon tissue of 20 patients with UC across multiple time points of disease. Corresponding clinical metadata was also obtained over the same time period for each patient to map their clinical disease course. The top ten most highly abundant clones from each time point were longitudinally tracked and correlated with disease phenotype. ResultsSeventy-five percent of patients did not have overlapping abundant TCR clones across multiple time points of disease. The remaining 25% of patients had one to five TCR clones present in high abundance in their tissue during every time point analyzed. ConclusionThese results demonstrate that most patients with UC do not share a similar TCR repertoire over time, indicating that times of inflammation are associated with unique antigen exposures. A smaller group of patients have persistent, private TCR clones with high abundance, 60% of whom had more unremitting, active disease.

immunology↗

bioRxiv2024

Aberrant N-glycosylation is a therapeutic target in carriers of a common and highly pleiotropic mutation in the manganese transporter ZIP8

The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDG). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense mutation in a manganese transporter ZIP8 has exposed under-appreciated roles for Mn homeostasis and aberrant Mn-dependent glycosyltransferases activity leading to defective N-glycosylation in complex human diseases. Here, we test the hypothesis that aberrant N-glycosylation contributes to disease pathogenesis of ZIP8 A391T-associated Crohns disease. Analysis of N-glycan branching in intestinal biopsies demonstrates perturbation in active Crohns disease and a genotype-dependent effect characterized by increased truncated N-glycans. A mouse model of ZIP8 391-Thr recapitulates the intestinal glycophenotype of patients carrying mutations in ZIP8. Borrowing from therapeutic strategies employed in the treatment of patients with CDGs, oral monosaccharide therapy with N-acetylglucosamine ameliorates the epithelial N-glycan defect, bile acid dyshomeostasis, intestinal permeability, and susceptibility to chemical-induced colitis in a mouse model of ZIP8 391-Thr. Together, these data support ZIP8 391-Thr alters N-glycosylation to contribute to disease pathogenesis, challenging the clinical paradigm that CDGs are limited to patients with rare diseases. Critically, the defect in glycosylation can be targeted with monosaccharide supplementation, providing an opportunity for genotype-driven, personalized medicine.

genomics↗

bioRxiv2023

Hepatobiliary manganese homeostasis is dynamic in the setting of illness in mice

Manganese is a diet-derived micronutrient that is essential for critical cellular processes like redox homeostasis, protein glycosylation, and lipid and carbohydrate metabolism. Control of Mn availability, especially at the local site of infection, is a key component of the innate immune response. Less has been elucidated about Mn homeostasis at the systemic level. In this work, we demonstrate that systemic Mn homeostasis is dynamic in response to illness in mice. This phenomenon is evidenced in male and female mice, mice of two genetic backgrounds (C57/BL6 and BALB/c), in multiple models of acute (dextran-sodium sulfate-induced) and chronic (enterotoxigenic Bacteriodes fragilis) colitis, and systemic infection with Candida albicans. When mice were fed a standard corn-based chow with excess Mn (100 ppm), liver Mn decreased and biliary Mn increased 3-fold in response to infection or colitis. Liver iron, copper, and zinc were unchanged. When dietary Mn was restricted to minimally adequate amounts (10ppm), baseline hepatic Mn levels decreased by approximately 60% in the liver, and upon induction of colitis, liver Mn did not decrease further, however biliary Mn still increased 20-fold. In response to acute colitis, hepatic Slc39a8 mRNA (gene encoding the Mn importer, Zip8) and Slc30a10 mRNA (gene encoding the Mn exporter, Znt10) are decreased. Zip8 protein is decreased. Illness- associated dynamic Mn homeostasis may represent a novel host immune/inflammatory response that reorganizes systemic Mn availability through differential expression of key Mn transporters with down-regulation of Zip8. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/533688v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a1db9aorg.highwire.dtl.DTLVardef@588af9org.highwire.dtl.DTLVardef@10be4b0org.highwire.dtl.DTLVardef@1d2eebc_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender.com

physiology↗

bioRxiv2021

Behavioral phenotyping of Zip8 393T-KI mice for in vivo study of schizophrenia pathogenesis

Genetic studies have informed on the genetic landscape of schizophrenia, and the next challenge is to link the genetic associations to mechanistic studies. A common single nucleotide polymorphism in the zinc and manganese transporter ZIP8 (rs13107325; ZIP8 A391T) is a top candidate to prioritize for functional studies because it is a missense mutation that results in hypomorphic protein function. With this goal, we have established a mouse model (Zip8 393T-knock-in (KI)), and here, we report the results of brain necropsy and initial behavioral phenotyping experiments in the KI mice using open field testing, elevated plus maze, Y-maze, and trace fear conditioning. Overall, male, homozygous KI mice may exhibit subtle defects in cognition and spatial learning, otherwise the baseline testing supports minimal behavioral differences between wild-type and Zip8 393T-KI mice. There were no genotype-specific alterations of gross or microscopic neuroanatomy. These experiments are important to establish the baseline characteristics of the Zip8 393T-KI mice that may be perturbed in animal models of schizophrenia and position the Zip8 393T-KI mouse as an important model for translational studies of schizophrenia pathogenesis.

genomics↗