An immunometabolic signature of major depressive disorder in systemic lupus erythematosus
Abstract
Background: Systemic lupus erythematosus (SLE) can affect the central nervous system, a condition known as neuropsychiatric SLE (NPSLE). NPSLE encompasses a variety of symptoms similar to those observed in major depressive disorder (MDD), which significantly worsens patients’ prognosis and quality of life. As MDD is associated with immunometabolic abnormalities, we investigated the immunobiology of MDDSLE. Methods: We studied 99 SLE patients from LUPIL-2, an international, multicentre, randomised, double-blind, placebo-controlled phase II trial of low-dose interleukin-2 (IL-2LD), and from the observational Transimmunom study, which includes 23 SLE patients, 257 patients with other immune-mediated diseases and 71 healthy volunteers (HV). Using clinical records and psychiatric scales, we first identified the depressed patients. Deep cell immunophenotyping and gut microbiome profiling were performed on patient blood and faecal samples. Unsupervised principal component analysis and supervised classification decision trees were used to identify an MDDSLE biological signature of LUPIL-2 patients, which was then validated using the Transimmunom study. Results: We identified an immunometabolic signature of MDDSLE with a classification prediction performance of 92%. This signature specifically associated ICOS+ effector memory regulatory T cells (Treg) and PD1+ CD4+ effector T cells (Teff) together with gut microbiota metabolic pathways of fatty acid and tryptophan biosynthesis. This signature efficiently identified MDDSLE patients from HV and SLE patients without MDD from the independent Transimunom study. Furthermore, this signature appeared to be specific for MDDSLE, as it did not separate patients with MDD associated with other immune-mediated diseases. Interpretation: Our findings support an immunometabolic basis of MDDSLE associated with Treg insufficiency and serotonin deficiency. They warrant further investigation of immunotherapies, including IL-2LD, for treating MDDSLE. Funding: Funding was provided by the French National Research Agency (ANR-11-IDEX-0004-02, LabEx Transimmunomand ANR-16-RHUS-0001, RHU IMAP to DK), the clinical study sponsor, ILTOO Pharma, and the INSERM (Contrat “Postes d’accueil” to PE). Declaration of Interest: MR, RL and DK are inventors for patent applications related to the therapeutic use of IL-2LD, which belongs to their academic institutions and has been licensed to ILTOO Pharma. MR and DK hold shares in ILTOO Pharma. No other potential conflicts of interest relevant to this article were reported. Ethical Approval: The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (ethics committee Ile-De France 48–15). Written informed consents were obtained from all participants before enrolment in the study.
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BibTeX
@article{ellul2026immunometabolic,
title = {{An immunometabolic signature of major depressive disorder in systemic lupus erythematosus}},
author = {Pierre Ellul and Nicolas Tchitchek and Grete Kvedaraviciute and Roberta Lorenzon and Isabelle Melki and Richard Delorme and Michelle Rosenzwajg and David Klatzmann},
journal = {Annals of the Rheumatic Diseases},
year = {2026},
month = oct,
doi = {10.1016/j.ard.2026.02.019},
url = {https://hal.science/hal-05798654v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - An immunometabolic signature of major depressive disorder in systemic lupus erythematosus
AU - Pierre Ellul
AU - Nicolas Tchitchek
AU - Grete Kvedaraviciute
AU - Roberta Lorenzon
AU - Isabelle Melki
AU - Richard Delorme
AU - Michelle Rosenzwajg
AU - David Klatzmann
PY - 2026
DA - 2026/10/14
JO - Annals of the Rheumatic Diseases
DO - 10.1016/j.ard.2026.02.019
UR - https://hal.science/hal-05798654v1
AB - Background: Systemic lupus erythematosus (SLE) can affect the central nervous system, a condition known as neuropsychiatric SLE (NPSLE). NPSLE encompasses a variety of symptoms similar to those observed in major depressive disorder (MDD), which significantly worsens patients’ prognosis and quality of life. As MDD is associated with immunometabolic abnormalities, we investigated the immunobiology of MDDSLE. Methods: We studied 99 SLE patients from LUPIL-2, an international, multicentre, randomised, double-blind, placebo-controlled phase II trial of low-dose interleukin-2 (IL-2LD), and from the observational Transimmunom study, which includes 23 SLE patients, 257 patients with other immune-mediated diseases and 71 healthy volunteers (HV). Using clinical records and psychiatric scales, we first identified the depressed patients. Deep cell immunophenotyping and gut microbiome profiling were performed on patient blood and faecal samples. Unsupervised principal component analysis and supervised classification decision trees were used to identify an MDDSLE biological signature of LUPIL-2 patients, which was then validated using the Transimmunom study. Results: We identified an immunometabolic signature of MDDSLE with a classification prediction performance of 92%. This signature specifically associated ICOS+ effector memory regulatory T cells (Treg) and PD1+ CD4+ effector T cells (Teff) together with gut microbiota metabolic pathways of fatty acid and tryptophan biosynthesis. This signature efficiently identified MDDSLE patients from HV and SLE patients without MDD from the independent Transimunom study. Furthermore, this signature appeared to be specific for MDDSLE, as it did not separate patients with MDD associated with other immune-mediated diseases. Interpretation: Our findings support an immunometabolic basis of MDDSLE associated with Treg insufficiency and serotonin deficiency. They warrant further investigation of immunotherapies, including IL-2LD, for treating MDDSLE. Funding: Funding was provided by the French National Research Agency (ANR-11-IDEX-0004-02, LabEx Transimmunomand ANR-16-RHUS-0001, RHU IMAP to DK), the clinical study sponsor, ILTOO Pharma, and the INSERM (Contrat “Postes d’accueil” to PE). Declaration of Interest: MR, RL and DK are inventors for patent applications related to the therapeutic use of IL-2LD, which belongs to their academic institutions and has been licensed to ILTOO Pharma. MR and DK hold shares in ILTOO Pharma. No other potential conflicts of interest relevant to this article were reported. Ethical Approval: The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (ethics committee Ile-De France 48–15). Written informed consents were obtained from all participants before enrolment in the study.
SN - 0003-4967
SN - 1468-2060
ER -