Dataset Information

Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.

ABSTRACT:

Background

Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1β-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-1β-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.

SUBMITTER: Hoffmann MC

PROVIDER: S-EPMC10794369 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.

Hoffmann Marie-Christin MC Cavalli Giulio G Fadle Natalie N Cantoni Eleonora E Regitz Evi E Fleser Octavian O Klemm Philipp P Zaks Marina M Stöger Elisabeth E Campochiaro Corrado C Tomelleri Alessandro A Baldissera Elena E Bittenbring Jörg Thomas JT Zimmer Vincent V Pfeifer Jochen J Fischer Yvan Y Preuss Klaus-Dieter KD Bewarder Moritz M Thurner Bernhard B Fuehner Sabrina S Foell Dirk D Dagna Lorenzo L Kessel Christoph C Thurner Lorenz L

Journal of clinical immunology 20240117 2

<h4>Background</h4>Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1β-driven disease of unknown etiology.<h4>Objective</h4>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.<h4>Methods</h4>Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA ...[more]

PMID: 38231276

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Project description:BackgroundInterleukin-1 receptor antagonist (IL-1RA), a member of the IL-1 family, has diverse roles in cancer development. However, the role of IL-1RA in oral squamous cell carcinoma (OSCC), in particular the underlying mechanisms, remains to be elucidated.MethodsTumor tissues from OSCC patients were assessed for protein expression by immunohistochemistry. Patient survival was evaluated by Kaplan-Meier curve analysis. Impact of differential IL-1RA expression on cultured OSCC cell lines was assessed in vitro by clonogenic survival, tumorsphere formation, soft agar colony formation, and transwell cell migration and invasion assays. Oxygen consumption rate was measured by Seahorse analyzer or multi-mode plate reader. PCR array was applied to screen human cancer stem cell-related genes, proteome array for phosphorylation status of kinases, and Western blot for protein expression in cultured cells. In vivo tumor growth was investigated by orthotopic xenograft in mice, and protein expression in xenograft tumors assessed by immunohistochemistry.ResultsClinical analysis revealed that elevated IL-1RA expression in OSCC tumor tissues was associated with increased tumor size and cancer stage, and reduced survival in the patient group receiving adjuvant radiotherapy compared to the patient group without adjuvant radiotherapy. In vitro data supported these observations, showing that overexpression of IL-1RA increased OSCC cell growth, migration/invasion abilities, and resistance to ionizing radiation, whereas knockdown of IL-1RA had largely the opposite effects. Additionally, we identified that EGFR/JNK activation and SOX2 expression were modulated by differential IL-1RA expression downstream of mitochondrial metabolism, with application of mitochondrial complex inhibitors suppressing these pathways. Furthermore, in vivo data revealed that treatment with cisplatin or metformin-a mitochondrial complex inhibitor and conventional therapy for type 2 diabetes-reduced IL-1RA-associated xenograft tumor growth as well as EGFR/JNK activation and SOX2 expression. This inhibitory effect was further augmented by combination treatment with cisplatin and metformin.ConclusionsThe current study suggests that IL-1RA promoted OSCC malignancy through mitochondrial metabolism-mediated EGFR/JNK activation and SOX2 expression. Inhibition of this mitochondrial metabolic pathway may present a potential therapeutic strategy in OSCC.

Dataset Information

Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.

Background

Objective

Methods

Results

Conclusion

Publications

Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.

Similar Datasets

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