Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.
J Clin Immunol
; 44(2): 45, 2024 Jan 17.
Article
em En
| MEDLINE
| ID: mdl-38231276
ABSTRACT
BACKGROUND:
Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1ß-driven disease of unknown etiology.OBJECTIVE:
In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still's disease.METHODS:
Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signaling reporter assay.RESULTS:
Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still's disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still's disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment.CONCLUSION:
Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still's disease patients, which is sensitive to high-dose IL-1 blocking therapy.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Juvenil
/
Proteína Antagonista do Receptor de Interleucina 1
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Clin Immunol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Alemanha