Biology subjects

Lazarev, M.

Publications and source records attributed to Lazarev, M..

2 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↗