The bidirectional interaction between the nervous and immune systems has been shown to be essential for both systems’ development and function, revealing that emotional states and brain activity can significantly influence immune responses and disease progression and vice versa. Inborn Errors of Immunity (IEI) represent a prime example of this crosstalk: they encompass a range of congenital disorders that detrimentally impair immune system’s function. but IEI patients often experience emotional distress and anxiety, traditionally assumed to result from their challenging health conditions. Therefore, the mechanisms linking IEI genetic alterations to the related neurological manifestations have been so far inadequately explored. In this study, we uncovered the neurodevelopmental origin of psychomotor deficits associated to IEI, untangling them from the immunodeficiency. We found that 30% of IEI is associated with neurological features, including neurodevelopmental delay, microcephaly and anxiety. Indeed, we showed that IEI genes are expressed in neural lineages of human brain, and in particular are enriched in the developing cerebellum, suggesting a direct role in cerebellar circuit formation. We addressed this point using as a paradigm a mouse model harboring the WHIM immunodeficiency-linked Cxcr4 mutation, which has been demonstrated to reproduce patients’ immune defects. We showed that, in absence of any immunological challenge, WHIM mice replicate the cerebellar morphological and behavioral alterations reported in patients. Our findings indicate that these defects have an early origin, as WHIM pups display altered cerebellar cytoarchitecture and follow atypical developmental trajectories. Single-cell profiling of newborn WHIM cerebellum revealed a major transcriptional deregulation in granule cell progenitors, triggering the observed long-lasting behavioral and functional defects. In support of this evidence, intracerebroventricular injection of a drug currently used in clinics at early embryonic stages rescues both morphological and behavioral defects, demonstrating that they stem directly from compromised Cxcr4 function within the developing brain. Collectively, our findings highlight the relevance of neurodevelopmental implications in the emergence of psychomotor symptoms, providing a novel perspective in patient management and demonstrating that IEI complexity extends beyond the immune system.
Neurodevelopmental origins of structural and psychomotor defects in WHIM immunodeficiency(2025 Jan 09).
Neurodevelopmental origins of structural and psychomotor defects in WHIM immunodeficiency
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2025-01-09
Abstract
The bidirectional interaction between the nervous and immune systems has been shown to be essential for both systems’ development and function, revealing that emotional states and brain activity can significantly influence immune responses and disease progression and vice versa. Inborn Errors of Immunity (IEI) represent a prime example of this crosstalk: they encompass a range of congenital disorders that detrimentally impair immune system’s function. but IEI patients often experience emotional distress and anxiety, traditionally assumed to result from their challenging health conditions. Therefore, the mechanisms linking IEI genetic alterations to the related neurological manifestations have been so far inadequately explored. In this study, we uncovered the neurodevelopmental origin of psychomotor deficits associated to IEI, untangling them from the immunodeficiency. We found that 30% of IEI is associated with neurological features, including neurodevelopmental delay, microcephaly and anxiety. Indeed, we showed that IEI genes are expressed in neural lineages of human brain, and in particular are enriched in the developing cerebellum, suggesting a direct role in cerebellar circuit formation. We addressed this point using as a paradigm a mouse model harboring the WHIM immunodeficiency-linked Cxcr4 mutation, which has been demonstrated to reproduce patients’ immune defects. We showed that, in absence of any immunological challenge, WHIM mice replicate the cerebellar morphological and behavioral alterations reported in patients. Our findings indicate that these defects have an early origin, as WHIM pups display altered cerebellar cytoarchitecture and follow atypical developmental trajectories. Single-cell profiling of newborn WHIM cerebellum revealed a major transcriptional deregulation in granule cell progenitors, triggering the observed long-lasting behavioral and functional defects. In support of this evidence, intracerebroventricular injection of a drug currently used in clinics at early embryonic stages rescues both morphological and behavioral defects, demonstrating that they stem directly from compromised Cxcr4 function within the developing brain. Collectively, our findings highlight the relevance of neurodevelopmental implications in the emergence of psychomotor symptoms, providing a novel perspective in patient management and demonstrating that IEI complexity extends beyond the immune system.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.