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

ABSTRACT: Primary immunodeficiency diseases (PIDDs) encompass a range of congenital disorders that adversely influence both innate and adaptive immune systems. While individuals diagnosed with PIDDs often exhibit elevated levels of emotional distress and neuropsychological challenges - such as depression and anxiety - the neurobiological underpinnings linking genetic alterations in PIDDs to their neurological manifestations have not been so far explored. Here, by mapping the expression of PIDD genes in transcriptional datasets sampling the human brain across multiple areas and ages, we identified a notable regional enrichment in the cerebellum, which encompasses neuronal and glial subtypes, extending beyond the immune cells. Aiming at elucidating the impact of PIDD genetic alterations on brain development, we focus on WHIM syndrome, caused by CXCR4 mutations. Consistently with clinical reports on WHIM patients, magnetic resonance imaging and histological analysis performed on WHIM mouse model showed distinct cerebellar foliation deficits associated with mild motor impairment and anxiety-like behavior from early development. Despite the restricted expression of CXCR4 in rhombic lip-derived progenitors, single-cell profiling uncovered a pervasive transcriptional alteration across various cerebellar cell types, well beyond the cell-autonomous effects of the mutation on the granule lineage. Significant downregulation of genes involved in dendrite branching and axonal elongation molecularly defined the reduced arborization observed in WHIM Purkinje cells, which is associated with altered lobule-specific frequency patterns by high-density multielectrode array recordings. In utero intraventricular administration of CXCR4 antagonist AMD3100 - currently in clinical trials in patients - successfully rescued both morphological and behavioral defects. This unravels a direct effect of the WHIM-associated Cxcr4-Cxcl12 axis on compromised cerebellar assembly of motor and anxiety-associated circuits. Our findings underscore the contribution of the cerebellum to emotional distress while emphasizing the importance of considering neurological implications in the management of PIDDs.

ORGANISM(S): Mus musculus

PROVIDER: GSE266671 | GEO | 2025/06/06

REPOSITORIES: GEO

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Project description:We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

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

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