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Immune Mechanisms of Human Disease (HUM)

Late-breaking: Immune Mechanisms of Human Disease

(206) Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency contributes to Treg Dysfunction and Susceptibility to Systemic Lupus Erythematosus

Saturday, April 18, 2026
2:30 PM - 3:30 PM US ET
Location: Exhibit Hall

    Author(s)

  • Limor Rubin, MD (she/her/hers)

    Post doctoral fellowship, MD
    Beth Israel Deaconess Medical Center, Harvard Medical School
    Brookline, Massachusetts, United States

Disclosure(s):
Limor Rubin, MD: No financial relationships to disclose
Introduction/Rationale: G6PD deficiency, the most common enzymopathy worldwide, is associated with an increased risk of systemic lupus erythematosus (SLE). The G6PD gene lies near SLE susceptibility genes such as IRAK1, and G6PD is the rate-limiting enzyme of the pentose phosphate pathway which is essential for the regulatory T cell (Treg) metabolism. Because impaired Treg cell function drives autoimmunity, we investigated how G6PD deficiency disrupts Treg cell function and promotes lupus pathogenesis.

Methods: Naïve CD4⁺ T cells from healthy donor PBMCs were treated with G6PD siRNA or a pharmacologic inhibitor and differentiated into iTreg cells. Treg cell function and metabolism were assessed using flow cytometry, suppression assays, Seahorse analysis and mass spectrometry-based metabolomics. Human studies included a single-center longitudinal cohort of adults with SLE (2006–2025) genomically tested for G6PD mutation status. Clinical outcomes were compared between mutation and non-mutation groups.

Results: G6PD inhibition or silencing reduced iTreg cell differentiation, impaired suppressive function, altered Treg metabolic profile and induced mitochondrial damage with increased levels of depolarized mitochondria. G6PD silencing in Treg cells lead to reduced NADPH, perturbation of the redox control, one-carbon metabolism, nucleotide balance, and amino-acid metabolism, all consistent with impaired pentose phosphate pathway activity and compensatory metabolic rewiring. In the SLE cohort, G6PD was reduced in SLE Tregs in comparison to healthy controls. G6PD mutations were associated with higher baseline disease activity (SLEDAI), and clinical visits.

Conclusion: G6PD deficiency disrupts Treg cell development and function through metabolic and non-metabolic mechanisms, contributing to SLE pathogenesis. These findings highlight a potential mechanistic link between a common enzymopathy and autoimmunity.