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Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I
Lorenzo Lodi1,2, Isabelle Melki1,3,4, Vincent Bondet5
1Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, 24 boulevard du Montparnasse, 75015, Paris, France.
Insights
Type I interferonopathies (T1Is) involve elevated interferon signaling, but central nervous system (CNS) involvement varies. This study found distinct sites of IFN-alpha production in monogenic T1Is, differentiating CNS involvement in Aicardi-Goutières syndrome versus peripheral production in SAVI.
Area of Science:
- Neuroimmunology
- Genetics
- Rheumatology
Background:
- Type I interferonopathies (T1Is) share upregulated type I interferon (IFN) signaling.
- Central nervous system (CNS) involvement differs among T1Is, with unclear underlying mechanisms.
- Understanding IFN production sites is crucial for diagnosing and treating T1Is.
Purpose of the Study:
- To investigate the primary sites of IFN-alpha production in various T1Is.
- To correlate IFN-alpha levels in cerebrospinal fluid (CSF) and serum with specific T1I diagnoses.
- To elucidate the basis for variable CNS involvement in T1Is.
Main Methods:
- Collected CSF and serum samples from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy (SAVI), other monogenic T1Is (pT1I), neuropsychiatric lupus (nSLE), non-IFN autoinflammation (AI), and controls.
- Quantified IFN-alpha protein levels using digital ELISA.
- Compared IFN-alpha concentrations between CSF and serum within individuals and across disease groups.
Main Results:
- Median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls.
- AGS showed higher IFN-alpha levels in CSF than in paired serum.
- SAVI, pT1I, and nSLE consistently had higher serum IFN-alpha levels compared to CSF.
- IFN-alpha was detected in both CSF and serum across all studied IFN-related diseases.
Conclusions:
- The primary site of IFN-alpha production in Aicardi-Goutières syndrome (AGS) is the CNS.
- The primary site of IFN-alpha production in STING-associated vasculopathy (SAVI) is the periphery.
- These findings differentiate monogenic T1Is and inform diagnostic and therapeutic strategies for T1Is.
Abstract:
Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
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