Biology subjects

Lizama Valenzuela, C.

Publications and source records attributed to Lizama Valenzuela, C..

3 recordsLinked to original sources

bioRxiv2026

AEGIS reveals epitope- and clone-resolved convergence of CNS B and T cell autoreactivity in ROHHAD

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

immunology↗

bioRxiv2025

Ex Vivo Expanded Regulatory T Cells Inhibit AAA Progression by Limiting CD4+ and CD8+ T Cell Accumulation in Aortic Tissue

BackgroundRegulatory T cells (Tregs) play a crucial role in the pathophysiology of abdominal aortic aneurysms (AAA), a chronic inflammatory condition with few treatment options for patients with early-stage disease. Treg therapy for AAA is potentially beneficial but its specific mechanism requires further investigation for clinical applications. MethodsAfter identifying the critical role of T-cells in AAA using human and mouse AAA single-cell RNA sequencing data, we investigated the influence of Tregs on immune cell infiltration within mouse AAA--specifically CD3+ T cells--using congenic transfer of Thy1.1 allelic donor mice Tregs into AAA-induced wild-type C57BL/6J mice. AAA progression was quantified with ultrasound and image micrometry. Tissues obtained on postoperative days 7-42 were analyzed with flow cytometry, qRT-PCR, Verhoeff-van Gieson staining, hematoxylin-eosin staining, and immunohistochemistry. ResultsCD3+ T cell population was profoundly elevated in the elastase induced AAA mouse model which was further used in the study. The AAA mice that received Treg cell therapy had less elastin degradation and aortic wall enlargement than their control counterparts. Donor Tregs were detected in draining lymph nodes even after five weeks, with characteristic expression of FOXP3 and CD25. Although donor Tregs were not detected in the aortic microenvironment, the pro-inflammatory cell population including CD4 and CD8 cells was reduced, compared to control mice. ConclusionElevated T cell population aggravates inflammation and promotes AAA progression. Treg therapy impedes the recruitment of T cells into AAA tissue by colonizing the draining lymph nodes, thereby mitigating AAA progression. This study deepens our understanding of Treg stability, function, and potential as a promising therapy for early-stage aneurysms.

immunology↗

bioRxiv2023

Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, we executed unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discovered a previously unappreciated mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism is dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of SEL1L. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus cell-autonomous, rheostatic collagen clearance is a previously unidentified pathway of tissue homeostasis.

cell biology↗