Unveiling the Neurobehavioral Implications of Inborn Error of Immunity Disorders: A Focus on WHIM Syndrome.

Inborn errors of immunity (IEI) are genetic disorders where the immune system is impaired from birth, leading to frequent infections. IEI patients show mental health issues, but the relationship between the brain and immune system is not well understood. We found that IEI genes are also expressed in neurons of the developing cerebellum, a brain region involved in motor function and cognition. Using a mouse model of the IEI WHIM syndrome, we discovered that the mutation causes motor deficits and anxiety-like behaviors. These symptoms, also observed in patients, were previously thought to be secondary to the frequent infections. However, our research shows that they are directly due to brain alterations. Treating WHIM mice with AMD3100, a drug already used in WHIM clinical trials, corrected both cerebellar structure and behaviors, indicating that these issues are directly caused by the mutation in the cerebellum. Our study has two main goals: (1) to understand how this genetic mutation affects brain development before birth by tracking the development of specific cerebellar neurons; (2) to assess how repeated infections, which WHIM patients often experience, worsen their symptoms. We will expose WHIM mice to infections and study the changes in their brains and behavior. Additionally, we will analyze patient data, brain scans, and mental health assessments to understand how these factors are connected. Overall, our research aims to establish a link between genetic mutations and neuropsychiatric symptoms in WHIM syndrome, to develop personalized treatments for patients.