A study led by Humanitas shows how some congenital immunodeficiencies directly influence cerebellar development and behavior, independently of infections or inflammation.

Primary immunodeficiencies (or Inborn Errors of Immunity, IEI) are rare genetic diseases affecting the immune system. Some of these chronic conditions, such as WHIM syndrome, are also associated with neurobehavioral disorders, often considered indirect consequences of recurrent infections patients experience since birth. However, a study just published in Neuron overturns this perspective: neurological alterations may originate directly during brain development and be caused by the very same genetic mutations that make the immune system dysfunctional.

Published in Neuron, the study was authored by a group of Humanitas researchers led by Simona Lodato, Associate Professor at Humanitas University and Head of the Neurodevelopment Laboratory at IRCCS Humanitas Research Hospital. The research – conducted also with the collaboration of neuroscientists, physicists, and immunologists from groups led by Michela Matteoli, Roberto Rusconi, and Marinos Kallikourdis – was supported by the prestigious ERC Starting Grant awarded to Simona Lodato in 2022, called IMPACT.

The role of the CXCR4 gene

Scientists demonstrated, so far in an experimental model of WHIM disease, that a mutation in the CXCR4 gene, responsible for the syndrome, disrupts normal cerebellar development already during the prenatal phase, causing defects in structure and behavior even in the absence of signs of inflammation.

“The anomalies concern the formation of cerebellar folds and are associated with reduced motor coordination and anxious behaviors, consistent with observations in some WHIM patients followed at Spedali Civili di Brescia by the team of our clinical collaborator Prof. Badolato,” explains Giulia Demenego, first author of the study, carried out during her PhD at Humanitas University. “Specifically, in our study, we show that hyperactivation of CXCR4 hinders migration and maturation of certain cerebellar neurons, altering crucial circuits for movement and emotion control.”

An experimental therapeutic approach

“The study results demonstrate that genes involved in immunodeficiencies, such as CXCR4, are also active in nerve cells during brain development, particularly in the cerebellum: a discovery with important implications for understanding and treating neurological symptoms in these patients,” states Simona Lodato.

The group also tested a possible therapeutic strategy: early treatment with a CXCR4 antagonist, administered during developmental phases and localized in the brain, was able to prevent structural defects and improve symptoms. CXCR4 is already used clinically for other predominantly immune-related purposes and is currently in clinical trials on adult WHIM patients, although at that stage it is too late to affect neuronal development.

“These results suggest that some neurological manifestations of congenital immunodeficiencies are not only a consequence of recurrent infections but may have direct neurological origins,” Lodato concludes. “This is a paradigm shift that calls for greater attention to the brain’s role in the study and management of these diseases.”

The study opens new perspectives for early identification and targeted treatment of neurological symptoms in congenital immunodeficiencies, but the researchers emphasize the need for further clinical studies, especially in pediatric populations, to translate these findings to humans. Research will continue with support from a recent Telethon grant awarded to the Lodato group.