Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation.

Humans Female Complement C1q / genetics Male Interferon Type I / metabolism Adult Child Adolescent Young Adult Signal Transduction Middle Aged Inflammation / genetics Interferon-alpha Child, Preschool Retrospective Studies

C1Q deficiency Complement Janus-kinase inhibition interferon neuroinflammation systemic lupus erythematosus

Journal

Journal of clinical immunology

ISSN: 1573-2592

Titre abrégé: J Clin Immunol

Pays: Netherlands

ID NLM: 8102137

Informations de publication

Date de publication:
28 Aug 2024

Historique:

received: 05 03 2024

accepted: 07 08 2024

medline: 28 8 2024

pubmed: 28 8 2024

entrez: 28 8 2024

Statut: epublish

Résumé

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.

Identifiants

DOI: 10.1007/s10875-024-01788-5 PMID: 39196411

pubmed: 39196411

doi: 10.1007/s10875-024-01788-5

pii: 10.1007/s10875-024-01788-5

doi:

Substances chimiques

Complement C1q 80295-33-6

Interferon Type I 0

Interferon-alpha 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

185

Informations de copyright

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