Chemical cartography identifies potential mechanistic, diagnostic, and therapeutic opportunities in RAG deficiency
5 affiliations
- 1Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- 2Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- 3Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health
- 4Division of Allergy and Immunology, Children’s Hospital of Philadelphia
- 5Neutrophil Monitoring Lab, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
Abstract
Background: Mutations in the recombination-activating genes (RAG1 and RAG2 ) in humans drive an array of immunodeficiencies with non-continuous symptom patterns. Previous multi-omic studies identified immune cell types and cytokines that defined RAG subtypes, but mechanisms remain to be established.
Objective: To use circulating metabolic and lipidomic patterns to further resolve drivers of symptom heterogeneity and suggest alternative therapeutic targets in RAG -mutated patients.
Method: RAG -mutated patient and healthy control plasma was analyzed across two cohorts using a chemical cartography approach wherein oxidative, dysbiotic, energetic, and neuroimmune patterns were broadly targeted through a series of overlaid immunometabolic and immunolipidomic profiling methods.
Results: Patterns in tryptophan metabolism, purine metabolism, lipid stress molecules, and oxylipin products of 12-lipoxygenase segregated disease subtypes and presented potential targets in RAG-disease pathology. Purine metabolism and certain lipid oxidation phenotypes were exacerbated after hematopoietic stem cell transplantation, suggesting continuing pathology after treatment.
Conclusions: This investigation reveals potentially targetable immune-related metabolic and lipidomic correlates of disease heterogeneity in human RAG-deficiency.
Related
- Innate immune cells in tumor immunity: dual roles, mechanistic insights, and therapeutic opportunities
- Cradle-to-gate life cycle assessment of pasteurized milk production in Uzbekistan identifies environmental hotspots and improvement opportunities
- Tumor microenvironment-driven immune evasion in triple-negative breast cancer: mechanisms, clinical challenges, and therapeutic opportunities
- Stem cell factor in allergic diseases: mechanisms of type 2 immunity and therapeutic opportunities
- Mapping a genome-scale in vivo knockout screen to a mechanistic network model identifies VAV2, RASA1, and LEPR as regulators of cardiomyocyte hypertrophy
BibTeX
@article{cooper2026chemical,
title = {{Chemical cartography identifies potential mechanistic, diagnostic, and therapeutic opportunities in RAG deficiency}},
author = {Gwendolyn Cooper and Ottavia M. Delmonte and Ian S. LaCroix and Dimana Dimitrova and Marita Bosticardo and Heather Kenney and Gloria Magro and Francesca Pala and Zixiao An and Jenna R. E. Bergerson and Alexandra F. Freeman and Jennifer R. Heimall and Steven M. Holland and Danielle Fink and Douglas B. Kuhns and Nathan T. Brandes and Eric Bohrnsen and Jade Uriarte and Benjamin Schwarz and Luigi D. Notarangelo},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1960496},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960496/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Chemical cartography identifies potential mechanistic, diagnostic, and therapeutic opportunities in RAG deficiency
AU - Gwendolyn Cooper
AU - Ottavia M. Delmonte
AU - Ian S. LaCroix
AU - Dimana Dimitrova
AU - Marita Bosticardo
AU - Heather Kenney
AU - Gloria Magro
AU - Francesca Pala
AU - Zixiao An
AU - Jenna R. E. Bergerson
AU - Alexandra F. Freeman
AU - Jennifer R. Heimall
AU - Steven M. Holland
AU - Danielle Fink
AU - Douglas B. Kuhns
AU - Nathan T. Brandes
AU - Eric Bohrnsen
AU - Jade Uriarte
AU - Benjamin Schwarz
AU - Luigi D. Notarangelo
PY - 2026
DA - 2026/10/23
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1960496
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960496/full
AB - Background: Mutations in the recombination-activating genes (RAG1 and RAG2 ) in humans drive an array of immunodeficiencies with non-continuous symptom patterns. Previous multi-omic studies identified immune cell types and cytokines that defined RAG subtypes, but mechanisms remain to be established. Objective: To use circulating metabolic and lipidomic patterns to further resolve drivers of symptom heterogeneity and suggest alternative therapeutic targets in RAG -mutated patients. Method: RAG -mutated patient and healthy control plasma was analyzed across two cohorts using a chemical cartography approach wherein oxidative, dysbiotic, energetic, and neuroimmune patterns were broadly targeted through a series of overlaid immunometabolic and immunolipidomic profiling methods. Results: Patterns in tryptophan metabolism, purine metabolism, lipid stress molecules, and oxylipin products of 12-lipoxygenase segregated disease subtypes and presented potential targets in RAG-disease pathology. Purine metabolism and certain lipid oxidation phenotypes were exacerbated after hematopoietic stem cell transplantation, suggesting continuing pathology after treatment. Conclusions: This investigation reveals potentially targetable immune-related metabolic and lipidomic correlates of disease heterogeneity in human RAG-deficiency.
SN - 1664-3224
ER -