Pierre Ellul

Maternal immune activation (MIA) and preterm birth have both been associated with increased risk of autism spectrum disorder but their combined impact in preterm children is unclear. This prospective population-based cohort study used data from the French EPIPAGE-2 study, which included liveborn infants delivered at 22 to 34 weeks’ gestation in 2011 and followed them to 5 years of age. Neurodevelopmental outcomes at 2 years’ corrected age and at 5 years were assessed. Among 3609 children (155 [4.3%] exposed), maternal autoimmune diseases were initially associated with more impaired personal-social skills on the Ages & Stages Questionnaire at 2 years and a lower prevalence of high Social Communication Questionnaire scores at 5 years, but these associations were no longer statistically significant after adjustment. No significant associations were found between maternal autoimmune diseases and global developmental delay, ASD risk, or behavioral difficulties at 2 or 5 years in adjusted analyses. Subgroup analyses by gestational age and by exposure to immunosuppressive therapy also showed no increased risk. In this national preterm birth cohort, maternal autoimmune diseases during pregnancy were not associated with increased early behavioral or social communication difficulties in offspring. However, given the small number of exposed children, the predominance of endocrine autoimmune diseases, and the lack of immune activation biomarkers, these findings should be interpreted cautiously and warrant confirmation in larger, mechanistically informed studies

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with complex genetic and environmental underpinnings. A clinically significant subset of children with ASD experience developmental regression ( _reg ASD), characterized by the acute loss of previously acquired skills. The mechanisms, predictors, and molecular basis of _reg ASD remain poorly understood. We retrospectively and prospectively analyzed a cohort of 505 children diagnosed with ASD at the Center of Excellence for Autism and Neurodevelopmental Disorders (Paris, France) between 2017 and 2023. Clinical, neurodevelopmental, and genetic data were collected, including detailed developmental histories, standardized diagnostic assessments (ADI‐R, ADOS‐2, VABS), and chromosomal microarray analysis (CMA). Statistical analyses included classification tree algorithms and principal component analysis to identify clinical predictors of regression, and gene ontology enrichment to explore molecular pathways. Developmental regression was detected in 74 children (15%). Prior to regression, _reg ASD children exhibited more favorable neurodevelopmental profiles, including lower rates of prematurity, higher birth weight and height, and earlier acquisition of first words, compared with nonregressive ASD (non‐ _reg ASD) peers. However, after regression, _reg ASD children had significantly more severe neurodevelopmental impairments across cognitive, adaptive, and social domains ( p < 0.001). Routine clinical variables did not reliably predict the onset of regression. CMA revealed that _reg ASD is associated with distinct genetic deletions enriched in immune, inflammatory (particularly Type I interferon), oxidative stress, angiogenesis, and synaptic pathways, with minimal overlap with non‐ _reg ASD genetic profiles. Our findings are consistent with the hypothesis that _reg ASD may represent a distinct clinical and molecular subgroup within ASD. The molecular signatures identified in _reg ASD suggest involvement of immune and synaptic pathways, highlighting the need for further targeted research to clarify their potential therapeutic implications for this subgroup.

Maternal immune activation (MIA) during pregnancy induces autism spectrum disorder (ASD)-like phenotypes in offspring. While maternal IL-17 signaling has been implicated in prenatal brain alterations, the postnatal mechanisms sustaining this phenotype remain unknown. Here, we show that MIA in mice imprints a persistent postnatal insufficiency of regulatory T cells (Tregs) in offspring, characterized by altered DNA methylation, transcriptional dysregulation, and impaired in vivo suppressive function. This Treg insufficiency drives sustained meningeal inflammation marked by infiltration of neutrophils and IL-17-producing immune cells, resulting in region-specific alterations in brain structure and functional connectivity. Functional MRI revealed hypoconnectivity in sensory networks together with hyperconnectivity in regions involved in emotional regulation, reward processing, and interhemispheric cognitive and motor integration. Postnatal stimulation of endogenous Tregs with low-dose interleukin-2 (IL-2) in MIA offspring expanded meningeal Tregs, eliminated IL-17-producing cells, resolved meningeal inflammation, normalized brain connectivity, and reversed MIA-induced ASD-like behaviors in adulthood. Extending these findings to humans, two children with ASD associated with documented maternal immune activation received treatment with low-dose IL-2 for six months. Treatment expanded circulating Tregs and was associated with marked and progressive clinical improvement across all assessed domains - social communication, socialization, interpersonal relationships, adaptive coping, and play. To our knowledge, this represents an unprecedented pharmacological improvement of core ASD symptoms. Together, our results redefine MIA-ASD as a chronic neuroimmune disorder amenable to therapeutic intervention, and establish Treg stimulation as a clinically actionable strategy with implications extending beyond autism to other MIA-associated neuropsychiatric disorders.

Implication des lymphocytes T régulateurs dans le trouble du spectre autistique secondaire à une activation immunitaire maternelle pendant la grossesse. Rationnel pour l'utilisation d'interleukine 2 faible dose à visée préventive et curative.Le trouble du spectre autistique (TSA) est une entité clinique hétérogène caractérisée par des troubles dans les interactions et la communication sociale et des comportements restreints et/ou stéréotypés. Son étiopathogénie repose sur l'interaction entre des facteurs de prédisposition génétique et des facteurs environnementaux. Parmi ces derniers, l'activation immunitaire maternelle durant la grossesse (MIA) augmente le risque de TSA dans la descendance. Il persiste cependant de nombreuses inconnues, à la fois fondamentales chez l'animal et cliniques chez l'Homme sur les mécanismes qui sous-tendent la persistance des symptômes autistiques. Afin de répondre à ces questions, nous avons combiné une approche épidémiologique et clinique, basée sur la cohorte de patients atteints de TSA pris en charge dans le centre d'excellence sur l'autisme et les troubles du neurodéveloppement de Robert Debré, avec une approche fondamentale sur un modèle murin de TSA en lien avec une MIA. Notre travail a mis en évidence, chez la souris, que la MIA entraine un défaut à long terme des lymphocytes T régulateurs (Tregs) dans la descendance entrainant une inflammation chronique du système nerveux central sous-tendant les symptômes autistiques. La stimulation des Tregs par de l'interleukine-2 à faible dose permet de normaliser les symptômes autistiques. Chez l'homme, nous avons également retrouvé ce défaut des Tregs et décrit que les TSA en lien avec un MIA représentent un sous-groupe homogène distinct des autres patients atteints de TSA. Nos résultats apportent un éclairage nouveau sur la physiopathologie du TSA en lien avec un MIA qui peut être considéré comme une maladie inflammatoire chronique du système nerveux central. Par ailleurs, ces patients représentent un sous-groupe identifiable dans l'hétérogénéité du TSA, ouvrant la voie au développement d'immunothérapie ciblant spécifiquement les Tregs, comme l'utilisation de l'interleukine-2 à faible dose.

Neurodevelopmental disorders affect a substantial proportion of children and represent a major public health challenge worldwide. Emerging evidence highlights complex interactions among genetic, environmental and immune factors — particularly during the critical window of neurodevelopmental vulnerability. These insights raise the possibility that children with juvenile systemic autoimmune and autoinflammatory diseases are at an increased risk of developing neurodevelopmental disorders. Early onset and delayed treatment of these autoimmune and autoinflammatory diseases seem to increase this vulnerability. Growing awareness of these associations is transforming paediatric rheumatology, highlighting the need for early screening, multidisciplinary management, and personalized interventions that target both inflammatory disease and neurodevelopment. International research collaborations, biomarker discovery and long-term follow-up are crucial for closing knowledge gaps and subsequently advancing care and outcomes. Recognizing and tackling neurodevelopmental disorders as frequent comorbidities of juvenile systemic autoimmune and autoinflammatory diseases is vital for improving educational attainment, psychosocial wellbeing and lifelong quality of life in children with chronic inflammatory conditions.

Maternal immune activation (MIA) and preterm birth have both been associated with increased risk of autism spectrum disorder but their combined impact in preterm children is unclear. This prospective population-based cohort study used data from the French EPIPAGE-2 study, which included liveborn infants delivered at 22 to 34 weeks’ gestation in 2011 and followed them to 5 years of age. Neurodevelopmental outcomes at 2 years’ corrected age and at 5 years were assessed. Among 3609 children (155 [4.3%] exposed), maternal autoimmune diseases were initially associated with more impaired personal-social skills on the Ages & Stages Questionnaire at 2 years and a lower prevalence of high Social Communication Questionnaire scores at 5 years, but these associations were no longer statistically significant after adjustment. No significant associations were found between maternal autoimmune diseases and global developmental delay, ASD risk, or behavioral difficulties at 2 or 5 years in adjusted analyses. Subgroup analyses by gestational age and by exposure to immunosuppressive therapy also showed no increased risk. In this national preterm birth cohort, maternal autoimmune diseases during pregnancy were not associated with increased early behavioral or social communication difficulties in offspring, suggesting that, in the context of contemporary antenatal care, such conditions may not confer additional early neurodevelopmental risk beyond that related to prematurity itself.