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Pyrin Inflammasome Activation Defines Colchicine-Responsive SURF Patients from FMF and Other Recurrent Fevers

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Abstract

Syndrome of undifferentiated recurrent fever (SURF) is characterized by recurrent fevers, a lack of confirmed molecular diagnosis, and a complete or partial response to colchicine. Despite the clinical similarities to familial Mediterranean fever (FMF), the underlying inflammatory mechanisms of SURF are not yet understood. We here analyzed the in vitro activation of the pyrin inflammasome in a cohort of SURF patients compared to FMF and PFAPA patients. Peripheral blood mononuclear cells (PBMC) were collected from SURF (both colchicine-treated and untreated), FMF, PFAPA patients, and healthy donors. PBMC were stimulated ex vivo with Clostridium difficile toxin A (TcdA) and a PKC inhibitor (UCN-01), in the presence or absence of colchicine. The assembly of the pyrin inflammasome was evaluated by measuring the presence of apoptosis-associated Speck-like protein containing caspase recruitment domain (ASC) specks in monocytes using flow cytometry. IL-1β secretion was quantified using an ELISA assay. No differences in TcdA-induced activation of pyrin inflammasome were observed among FMF, PFAPA, and healthy donors. Untreated SURF patients showed a reduced response to TcdA, which was normalized after colchicine treatment. In contrast to FMF, SURF patients, similar to PFAPA patients and healthy donors, did not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. These data demonstrate that in vitro functional analysis of pyrin inflammasome activation can differentiate SURF from FMF and PFAPA patients, suggesting the involvement of the pyrin inflammasome in the pathophysiology of SURF.

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Funding

The study has been supported by Ricerca Corrente of the Italian Ministry of Health.

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Authors and Affiliations

  1. UOC Reumatologia E Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Serena Palmeri, Federica Penco, Arinna Bertoni, Marta Bustaffa, Caterina Matucci-Cerinic, Riccardo Papa, Enrico Drago, Roberta Caorsi, Anna Corcione, Paola Bocca, Cristina Scarone, Stefano Volpi, Marco Gattorno & Ignazia Prigione

  2. Dipartimento Di Neuroscienze, Riabilitazione, OftalmologiaGenetica e Scienze Materno-Infantili (DINOGMI), Università Degli Studi Di Genova, Genoa, Italy

    Serena Palmeri, Enrico Drago & Stefano Volpi

  3. IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Anna Rubartelli

Authors
  1. Serena Palmeri
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  2. Federica Penco
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Contributions

IP, MG, and SP conceived the study. IP and MG were responsible for study supervision. SP and IP coordinated the study and acquired data. FP, AB, and AC performed cytokine assays. PB and CS participated in sample collection. MB, CM-C, RP, RC, ED, and SV participated in patient evaluation and selection. All authors have contributed in a substantial and intellectual manner to this manuscript; SP, IP, AR, and MG wrote the essential sections of the manuscript, which was critically revised by all authors.

Corresponding author

Correspondence to Marco Gattorno.

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Ethical Approval

The study protocol was approved by the Ethical board of the G. Gaslini Institute in Genova (Italy).

Consent to Participate

Written informed consent was obtained from all participants included in the study. In case of minor patients, written informed consent was obtained from the parents.

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Not applicable.

Competing Interests

MG has received consultant and speaker honoraria from Novartis and SOBI. All other authors declare they have no financial interests.

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Palmeri, S., Penco, F., Bertoni, A. et al. Pyrin Inflammasome Activation Defines Colchicine-Responsive SURF Patients from FMF and Other Recurrent Fevers. J Clin Immunol 44, 49 (2024). https://doi.org/10.1007/s10875-023-01649-7

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