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The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome

INTRODUCTION: Schnitzler’s syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. Anti-interleukin-1 (IL-1) beta antibodies are highly effective, but the pathophysiology is still largel...

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Autores principales: de Koning, Heleen D., Schalkwijk, Joost, Stoffels, Monique, Jongekrijg, Johanna, Jacobs, Joannes F. M., Verwiel, Eugène, Koenen, Hans J. P. M., Preijers, Frank, Holzinger, Dirk, Joosten, Irma, van der Meer, Jos W. M., Simon, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511239/
https://www.ncbi.nlm.nih.gov/pubmed/26198339
http://dx.doi.org/10.1186/s13075-015-0696-0
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author de Koning, Heleen D.
Schalkwijk, Joost
Stoffels, Monique
Jongekrijg, Johanna
Jacobs, Joannes F. M.
Verwiel, Eugène
Koenen, Hans J. P. M.
Preijers, Frank
Holzinger, Dirk
Joosten, Irma
van der Meer, Jos W. M.
Simon, Anna
author_facet de Koning, Heleen D.
Schalkwijk, Joost
Stoffels, Monique
Jongekrijg, Johanna
Jacobs, Joannes F. M.
Verwiel, Eugène
Koenen, Hans J. P. M.
Preijers, Frank
Holzinger, Dirk
Joosten, Irma
van der Meer, Jos W. M.
Simon, Anna
author_sort de Koning, Heleen D.
collection PubMed
description INTRODUCTION: Schnitzler’s syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. Anti-interleukin-1 (IL-1) beta antibodies are highly effective, but the pathophysiology is still largely unknown. Here we studied the effect of in-vivo IL-1 inhibition on serum markers of inflammation and cellular immune responses. METHODS: Eight patients with SchS received monthly subcutaneous (s.c.) injections with 150 mg canakinumab for six months. Blood was drawn for measurement of serum markers of inflammation (12 times per patient) and for functional and phenotypic analysis of both freshly isolated and toll-like receptor (TLR)-ligand-stimulated peripheral blood mononuclear cells (PBMCs) (five times per patient). All data were compared to results of healthy controls. RESULTS: IL-6 levels in serum and in lysates of freshly isolated PBMCs and serum myeloid-related protein (MRP8)/14 and S100A12 levels correlated with disease activity. In vitro, LPS stimulation resulted in higher IL-6 and IL-1 beta production in PBMCs from symptomatic SchS patients compared to healthy controls, whereas patient cells were relatively hyporesponsive to poly:IC and Pam3Cys. The mRNA microarray of PBMCs showed distinct transcriptomes for controls, symptomatic patients and anti-IL-1-treated patients. Numbers of T- and B-cell subsets as well as M-protein concentrations were not affected by IL-1 inhibition. Free light chain levels were elevated in 4 out of 8 patients. CONCLUSIONS: In conclusion, patient PBMCs are hyperresponsive to LPS, and clinical efficacy of IL-1 beta inhibition in patients with SchS is associated with in-vivo and ex-vivo suppression of inflammation. Interestingly, patient PBMCs showed divergent responses to TLR2/6, TLR3 and TLR4 ligands. Our data underscore that IL-1 beta plays a pivotal role in SchS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-015-0696-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-45112392015-07-23 The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome de Koning, Heleen D. Schalkwijk, Joost Stoffels, Monique Jongekrijg, Johanna Jacobs, Joannes F. M. Verwiel, Eugène Koenen, Hans J. P. M. Preijers, Frank Holzinger, Dirk Joosten, Irma van der Meer, Jos W. M. Simon, Anna Arthritis Res Ther Research Article INTRODUCTION: Schnitzler’s syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. Anti-interleukin-1 (IL-1) beta antibodies are highly effective, but the pathophysiology is still largely unknown. Here we studied the effect of in-vivo IL-1 inhibition on serum markers of inflammation and cellular immune responses. METHODS: Eight patients with SchS received monthly subcutaneous (s.c.) injections with 150 mg canakinumab for six months. Blood was drawn for measurement of serum markers of inflammation (12 times per patient) and for functional and phenotypic analysis of both freshly isolated and toll-like receptor (TLR)-ligand-stimulated peripheral blood mononuclear cells (PBMCs) (five times per patient). All data were compared to results of healthy controls. RESULTS: IL-6 levels in serum and in lysates of freshly isolated PBMCs and serum myeloid-related protein (MRP8)/14 and S100A12 levels correlated with disease activity. In vitro, LPS stimulation resulted in higher IL-6 and IL-1 beta production in PBMCs from symptomatic SchS patients compared to healthy controls, whereas patient cells were relatively hyporesponsive to poly:IC and Pam3Cys. The mRNA microarray of PBMCs showed distinct transcriptomes for controls, symptomatic patients and anti-IL-1-treated patients. Numbers of T- and B-cell subsets as well as M-protein concentrations were not affected by IL-1 inhibition. Free light chain levels were elevated in 4 out of 8 patients. CONCLUSIONS: In conclusion, patient PBMCs are hyperresponsive to LPS, and clinical efficacy of IL-1 beta inhibition in patients with SchS is associated with in-vivo and ex-vivo suppression of inflammation. Interestingly, patient PBMCs showed divergent responses to TLR2/6, TLR3 and TLR4 ligands. Our data underscore that IL-1 beta plays a pivotal role in SchS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-015-0696-0) contains supplementary material, which is available to authorized users. BioMed Central 2015-07-22 2015 /pmc/articles/PMC4511239/ /pubmed/26198339 http://dx.doi.org/10.1186/s13075-015-0696-0 Text en © de Koning et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
de Koning, Heleen D.
Schalkwijk, Joost
Stoffels, Monique
Jongekrijg, Johanna
Jacobs, Joannes F. M.
Verwiel, Eugène
Koenen, Hans J. P. M.
Preijers, Frank
Holzinger, Dirk
Joosten, Irma
van der Meer, Jos W. M.
Simon, Anna
The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome
title The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome
title_full The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome
title_fullStr The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome
title_full_unstemmed The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome
title_short The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome
title_sort role of interleukin-1 beta in the pathophysiology of schnitzler’s syndrome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511239/
https://www.ncbi.nlm.nih.gov/pubmed/26198339
http://dx.doi.org/10.1186/s13075-015-0696-0
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