The team's overarching objective is to understand the molecular and cellular mechanisms that maintain lymphocyte homeostasis and immune self-tolerance, and to determine how their disruption leads to primary immune deficiencies and dysregulations (PIDD) associated with early-onset autoimmunity and autoinflammation. By combining in-depth clinical characterization of patients presenting with rare, often previously undiagnosed immune disorders with genetic, cellular and multi-omics approaches, the team seeks to identify new disease-causing genes and pathways, to understand their impact on immune homeostasis, and to translate these discoveries into improved diagnosis and targeted treatment for patients.
This research program is organized around several complementary lines of investigation, each grounded in the study of patient cohorts followed at Necker–Enfants Malades Hospital as well as in other national reference centers.
Fas-mediated apoptosis and the autoimmune lymphoproliferative syndrome (ALPS)
The team discovered the first genetic cause of human autoimmunity, describing dominant-negative germline mutations of the FAS gene in patients with the autoimmune lymphoproliferative syndrome (ALPS). It subsequently identified the first somatic FAS mutations in sporadic forms of the disease, and later showed how the combination of germline and somatic FAS or FADD mutations within a single family explains the incomplete, non-Mendelian penetrance of ALPS, a genetic framework that continues to guide the diagnosis of ALPS, Evans syndrome and related cytopenias today.
RAS-pathway disorders in childhood: from RALD to juvenile myelomonocytic leukaemia (JMML)
Somatic activating mutations of KRAS or NRAS in the hematopoietic stem cell give rise to two very different childhood blood disorders: juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative malignancy, and RAS-associated autoimmune leukoproliferative disease (RALD), a chronic, indolent condition associated with autoimmune manifestations that can, in some patients, progress to JMML. The team has shown that this transition from RALD to JMML is accompanied by a loss of FAS-FASLG-mediated apoptotic checkpoints in the T-cell compartment, an apoptosis defect that is reversible and appears to be actively induced by the malignant myeloid clone. Building on this discovery, and combining single-cell transcriptomic and epigenomic analyses with in vitro co-culture systems of malignant myeloid and T cells, the team is now dissecting how malignant cells could impact the apoptosis pathway and evade T-cell-mediated control, with the aim of identifying biomarkers of malignant transformation and therapeutic strategies to restore the FAS-FASLG checkpoint in JMML.
Somatic KRAS mutations and inflammation in chronic myelomonocytic leukaemia (CMML-SIAD)
In collaboration with Professor Éric Solary's team, experts in chronic myelomonocytic leukaemia (CMML), this project, coordinated by Dr Jérome Hadjadj, investigates why up to 30% of patients with CMML develop severe systemic inflammatory and autoimmune manifestations (SIAD), a complication that remains poorly understood and often resistant to conventional treatment. Using a multicentre cohort of more than 90 patients with CMML-SIAD, the team showed a marked enrichment of somatic mutations of the RAS-MAPK pathway in these patients. The project now combines single-cell and long-read sequencing of patient samples with base-edited human CD34+ stem-cell models of RAS-MAPK mutations, and pharmacological screening to define the mechanisms linking these mutations to inflammation and to identify targeted therapeutic strategies for this severe subgroup of patients.
Type I interferon signaling: the discovery of STING1-related disease
The team identified the first inherited, activating mutations of STING1, causing a severe inflammatory vasculopathy with lung fibrosis and lupus-like features in children. This discovery directly led to the repurposing of JAK inhibitors as an effective, targeted treatment for affected patients, a striking illustration of the bedside-to-bench-to-bedside cycle that characterizes the team's approach.
Cytokine signaling and systemic autoimmunity: SOCS1, PTPN2 and JAK1
Further work identified SOCS1 haploinsufficiency and, more recently, PTPN2 haploinsufficiency and gain-of-function JAK1 mutations, as causes of early-onset systemic autoimmunity spanning a clinical spectrum from Evans syndrome to lupus and psoriasis. In each case, hyperactivation of the JAK-STAT signaling pathway provided a direct molecular rationale for treating patients with JAK inhibitors.
Cytoskeletal regulation of immunity: DOCK11
The team recently described hemizygous mutations in DOCK11 as a novel cause of X-linked actinopathy associated with autoimmune disease, extending the genetic landscape of immune dysregulation to regulators of the actin cytoskeleton. Building on this discovery, ongoing work aims to identify biomarkers of this condition and to characterize further, still unresolved genetic causes of actinopathies currently under investigation in the team's patient cohort.
Immuno-metabolic mechanisms in pediatric autoimmune hepatitis
Combining whole-exome sequencing with functional immune studies, the team identified rare, damaging variants in genes controlling the mTORC1 signaling pathway (including MTOR, TSC2, RRAGC, LAMTOR3 and PRKAG1) in children with autoimmune hepatitis, and showed that hyperactivation of this pathway is a recurrent feature of the disease, even in the absence of an identified causal variant, an activation that could be reversed in vitro by mTOR inhibitors. This project, coordinated by Dr Aude Magerus, in close partnership with the national reference centres for pediatric and adult autoimmune hepatitis at Bicêtre and Necker hospitals, is now focusing, in a cohort of nearly 100 children, on the immune–metabolic interactions between the liver and the immune system, combining long-read whole-genome sequencing, single-cell and spatial transcriptomics of liver biopsies, multiplexed tissue imaging and co-culture models derived from patients' induced pluripotent stem cells, with the aim of identifying new biomarkers and paving the way towards precision, mTOR-pathway-targeted therapy.
Autoimmune cytopenias: pediatric and adult Evans syndrome
In collaboration with the coordinating centre of the French national reference network for pediatric autoimmune cytopenias (CEREVANCE, Dr Nathalie Aladjidi), the team has established a prospective cohort of more than 200 children with early-onset Evans syndrome, the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Systematic genetic screening in this cohort identified a genetic cause in nearly half of tested patients, encompassing both well-established primary immunodeficiency genes (including FAS, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1 and KRAS) and numerous novel candidate genes not previously linked to autoimmune disease, with direct prognostic and therapeutic implications. In collaboration with the national reference centre for adult autoimmune cytopenias (CeReCAI, Pr Bertrand Godeau), the team extended this genetic approach to adult-onset Evans syndrome, confirming the contribution of constitutional genetic variants, including gain-of-function STAT3 mutations amenable to JAK-inhibitor treatment, in a subset of adult patients. Building on these findings, the team is now pursuing systematic exome and multi-omics profiling across the full pediatric cohort to identify further, still unknown genetic causes of Evans syndrome and to search for cellular and molecular biomarkers able to predict disease severity, relapse and response to targeted treatment.
Genetics of systemic lupus erythematosus and antinuclear antibodies as a pathogenic modifier
The team is a partner of the GENIAL national cohort (coordinated by Pr Alexandre belot) of childhood-onset systemic lupus erythematosus (jSLE) and uses exome sequencing to identify monogenic causes of the disease. In the largest exome-based study of unselected jSLE to date, involving 172 families, this collaborative effort established a molecular diagnosis in 10% of patients, confirming the contribution of lupus genes discovered by the team, including SOCS1, PTPN2 and DOCK11, and identifying novel candidate genes, further illustrating the marked genetic heterogeneity of the disease and supporting systematic genetic testing in patients with early-onset or syndromic lupus.
Beyond genetic predisposition, the team investigates how antinuclear antibodies, and in particular anti-double-stranded DNA (anti-dsDNA) antibodies, a diagnostic hallmark and activity marker of lupus, actively contribute to disease pathogenesis.
The EVAH project: enteric virus-associated hepatitis
The team also contributes to the EVAH project (Enteric Virus-Associated Hepatitis), coordinated by Prof. Bénédicte Neven and Dr Quentin Riller in partnership with the microbiology laboratory of Necker Children's Hospital and the WHO Collaborating Centre for Enteroviruses at Institut Pasteur. The project builds on the team's observation that patients transplanted for severe combined immunodeficiency can develop late-onset chronic hepatitis associated with persistent digestive shedding of enteric viruses (norovirus, sapovirus, Aichi virus) and an expansion of activated effector-memory CD8+ T cells. Using viral metagenomics, mass cytometry and single-cell transcriptomics, the team aims to establish the causal role of chronic enteric viral infection in this immunopathological condition, and to determine whether it also underlies liver disease in other antibody deficiencies, such as common variable immunodeficiency and agammaglobulinaemia.
Multi-omics and AI-assisted diagnosis: the RHU consortium
The team coordinates a national consortium project funded by the 4th RHU call (€9.9 million, 2020–2026), developing AI-based tools to reduce diagnostic wandering and guide clinical decision-making in primary immune disorders associated with autoimmunity and autoinflammation. This project relies on the integration of multi-omics data (genomic, transcriptomic and proteomic) with detailed clinical and immunological phenotyping, an approach made possible by the close collaboration with Dr Mickaël Ménager's laboratory. Building on this experience, multi-omics profiling is now increasingly applied across the team's other research lines, helping to capture the cellular and molecular heterogeneity of these rare diseases and to accelerate the discovery of new susceptibility genes.