Neuroinflammation Associated With Inborn Errors of Immunity

Abstract

The advent of high-throughput sequencing has facilitated genotype-phenotype correlations in congenital diseases. This has provided molecular diagnosis and benefited patient management but has also revealed substantial phenotypic heterogeneity. Although distinct neuroinflammatory diseases are scarce among the several thousands of established congenital diseases, elements of neuroinflammation are increasingly recognized in a substantial proportion of inborn errors of immunity, where it may even dominate the clinical picture at initial presentation. Although each disease entity is rare, they collectively can constitute a significant proportion of neuropediatric patients in tertiary care and may occasionally also explain adult neurology patients. We focus this review on the signs and symptoms of neuroinflammation that have been reported in association with established pathogenic variants in immune genes and suggest the following subdivision based on proposed underlying mechanisms: autoinflammatory disorders, tolerance defects, and immunodeficiency disorders. The large group of autoinflammatory disorders is further subdivided into IL-1β-mediated disorders, NF-κB dysregulation, type I interferonopathies, and hemophagocytic syndromes. We delineate emerging pathogenic themes underlying neuroinflammation in monogenic diseases and describe the breadth of the clinical spectrum to support decisions to screen for a genetic diagnosis and encourage further research on a neglected phenomenon.

The role of type I IFN in autoimmune and autoinflammatory diseases with CNS involvement

“…Zhang and colleagues demonstrated that patients with ISG15 -deficient displayed clinical signs of enhanced IFN-α/β immunity as seen in AGS and spondyloenchondrodysplasia (SPENCD) such as cerebral calcifications (nearly 100% of patients with ISG15) and sporadic reports of seizures. It was further shown by the same group that the absence of intracellular ISG15 prevents the accumulation of USP18 thereby sustaining the effect of IFN-α/β inflammation ( 105 , 117 ). ISG15 also acts as an extracellular inducer of type II IFN and, therefore, its deficiency is subsequently associated with increased susceptibility to mycobacterial disease ( 117 ).…”

“…It was further shown by the same group that the absence of intracellular ISG15 prevents the accumulation of USP18 thereby sustaining the effect of IFN-α/β inflammation ( 105 , 117 ). ISG15 also acts as an extracellular inducer of type II IFN and, therefore, its deficiency is subsequently associated with increased susceptibility to mycobacterial disease ( 117 ). It was later shown that myeloid cells (monocytes and DCs) were the primary responders to IFN-I-mediated inflammation in the peripheral blood of patients with ISG15 deficiency ( 118 ).…”

“…DNase II deficiency is a distinct clinical entity of autoinflammation and elevated type I IFN signaling. Neurological manifestations include once more cerebral calcifications and WMH ( 117 ).…”

“…Among other clinical manifestations, neurological involvement such as intracranial calcification and immune dysregulation manifesting through autoimmune diseases or immunodeficiency are also present ( 120 ). Loss-of-function mutations in the ACP5 gene ( 117 ) which encodes tartrate-resistant acid phosphatase (TRAP) was identified as the genetic cause of SPENCD. As a consequence, the deficit in TRAP leads to elevated levels of phosphorylated osteopontin, which in turn results in dysregulated endochondral ossification but also increased type I IFN signature ( 120 ).…”

“…In addition, the elevated type I IFN signature found in patients with CANDLE may be a key mediator of the inflammatory response and serve as a therapeutic target ( 108 ). CANDLE is now classified under the subcategory of interferonopathies called proteasome-related autoinflammation (PRAAS1) and is called PRAAS1 ( 117 ). The ubiquitin-proteasome system (UPS) is involved in various cellular functions such as misfolded protein clearance, MHC class I antigen processing, and others ( 122 ).…”