Neurodevelopmental origins of structural and psychomotor defects in CXCR4-linked primary immunodeficiency

Inborn errors of immunity (IEI), as congenital chronic disorders, are often associated with neurobehavioral symptoms, traditionally considered secondary to patient burden. Their origin, however, has yet to be addressed. Here, we found that IEI-associated genes are expressed in neural lineages during human brain development, and in the absence of immunological challenges, IEI mutations directly impair neurodevelopmental trajectories, leading to psychomotor defects. Warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) mice-bearing a mutation causing Cxcr4 hyperactivation-show developmental foliation defects of the cerebellum correlating with sensorimotor and affective dysfunctions, which recapitulate the alterations described in patients. WHIM cerebella single-cell profiling revealed major transcriptional deregulation in granule cell progenitors, whose aberrant proliferation and migration induce foliation and circuit defects. AMD3100 intracerebroventricular injection rescues both morphological and behavioral defects, demonstrating their brain-specific and Cxcr4-dependent origin. Collectively, our findings highlight the relevance of neurodevelopmental implications underlying psychomotor IEI manifestations, broadening our understanding of these conditions beyond immune dysfunctions.

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Publication Details

Journal
Neuron
Published
2025-06-06
DOI
https://doi.org/10.1016/j.neuron.2025.05.016
Citations
4
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
3.19
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article

Neurodevelopmental origins of structural and psychomotor defects in CXCR4-linked primary immunodeficiency

Luca Pellegrino, Diana Cash, Antonella Borreca, Sara Mancinelli et al.
4 citations
Neuron
Immunodeficiency and Autoimmune Disorders
3.19
article

Neurodevelopmental origins of structural and psychomotor defects in CXCR4-linked primary immunodeficiency

Luca Pellegrino, Diana Cash, Antonella Borreca, Sara Mancinelli, Marinos Kallikourdis, Roberto Rusconi, Katarina Ilić, Irene Corradini, Lucia Zucchelli, Michela Matteoli, Raffaele Badolato, M. Cremonesi, Simona Lodato, Davide Pozzi, Vanessa Aragona, Giulia Demenego, Matteo Miotto, Eugene Kim, Rosalba Olga Proce, Edoardo Fraviga
article en
4 citations

Abstract

Inborn errors of immunity (IEI), as congenital chronic disorders, are often associated with neurobehavioral symptoms, traditionally considered secondary to patient burden. Their origin, however, has yet to be addressed. Here, we found that IEI-associated genes are expressed in neural lineages during human brain development, and in the absence of immunological challenges, IEI mutations directly impair neurodevelopmental trajectories, leading to psychomotor defects. Warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) mice-bearing a mutation causing Cxcr4 hyperactivation-show developmental foliation defects of the cerebellum correlating with sensorimotor and affective dysfunctions, which recapitulate the alterations described in patients. WHIM cerebella single-cell profiling revealed major transcriptional deregulation in granule cell progenitors, whose aberrant proliferation and migration induce foliation and circuit defects. AMD3100 intracerebroventricular injection rescues both morphological and behavioral defects, demonstrating their brain-specific and Cxcr4-dependent origin. Collectively, our findings highlight the relevance of neurodevelopmental implications underlying psychomotor IEI manifestations, broadening our understanding of these conditions beyond immune dysfunctions.

NeuronVol. 113(16)
Helmholtz Association of German Research Centres (DE), Humanitas University (IT), Wellcome Centre for Human Neuroimaging (GB), King's College London (GB), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), IRCCS Humanitas Research Hospital (IT), University of Brescia (IT)
Good health and well-being
Openalex Percentile: Top 8%
Immunodeficiency and Autoimmune Disorders
3.19
DOIOpen Access PDFOpenAlex
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