Inborn errors of immunity (IEI) are increasingly recognized not only as disorders of infection susceptibility but also as systemic diseases with diverse manifestations across multiple organs. The central nervous system (CNS) is a major site of involvement, and neurological manifestations in IEI may arise through a variety of mechanisms, including infection, autoinflammation, immune dysregulation, vasculopathy, and lymphoproliferative disease.
Among infection-related complications, bacterial meningitis associated with MYD88 or IRAK4 deficiency represents a classic example. In autoinflammatory disorders, including NLRP3-associated disease, a broad spectrum of CNS inflammation has been described, such as aseptic meningitis and white matter lesions. In ADA2 deficiency, vasculopathy-related cerebral infarction is a characteristic neurological manifestation.
Familial hemophagocytic lymphohistiocytosis (FHL) provides another important example of CNS involvement in IEI. Neurological manifestations in FHL3 have long been recognized. More recently, patients with FHL2 carrying PRF1 missense variants have been reported to develop slowly progressive CNS lesions during adolescence or adulthood, in some cases preceding the onset of hemophagocytic lymphohistiocytosis (HLH). In addition, several patients showing pontine punctate and curvilinear contrast enhancement characteristic of CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) have been found to carry a hypomorphic variant in one UNC13D allele, without necessarily developing overt HLH. These observations suggest a potentially novel phenotype linking partial impairment of lymphocyte cytotoxicity to CNS-restricted inflammation.
In this seminar, I will review the neurological spectrum of IEI as a manifestation of systemic immune dysfunction and highlight recent advances that are reshaping our understanding of CNS pathology in these disorders.
