Clinical and genetic characterization of Italian patients affected by CINCA syndrome

Caroli, Francesco; Pontillo, Alessandra; D’Osualdo, Andrea; Travan, Laura; Ceccherini, Isabella; Crovella, Sérgio; Alessio, M; Stabile, Achille; Gattorno, Marco; Tommasini, Alberto; Martini, Alberto; Lepore, Loredana

doi:10.1093/rheumatology/kel269

Cited by 65 publications

(47 citation statements)

References 33 publications

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“…Among the patients examined in this study, C5 lacked NLRP3 mutations but displayed clinical manifestations clearly consistent with a CINCA syndrome (29) and the same redox alterations observed in mutated CINCA monocytes (Figs. 2 and 3).…”

Section: Discussionsupporting

confidence: 58%

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Tassi¹,

Carta²,

Delfino³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

131

159

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In healthy monocytes, Toll-like receptor (TLR) engagement induces production of reactive oxygen species (ROS), followed by an antioxidant response involved in IL-1β processing and secretion. Markers of the antioxidant response include intracellular thioredoxin and extracellular release of reduced cysteine. Cryopyrinassociated periodic syndromes (CAPS) are autoinflammatory diseases in which Nod-like receptor family pyrin domain-containing 3 (NLRP3) gene mutations lead to increased IL-1β secretion. We show in a large cohort of patients that IL-1β secretion by CAPS monocytes is much faster than that by healthy monocytes. This accelerated kinetics is caused by alterations in the basal redox state, as well as in the redox response to TLR triggering displayed by CAPS monocytes. Indeed, unstimulated CAPS monocytes are under a mild oxidative stress, with elevated levels of both ROS and antioxidants. The redox response to LPS is quickened, with early generation of the reducing conditions favoring IL-1β processing and secretion, and then rapidly exhausted. Therefore, secretion of IL-1β is accelerated, but reaches a plateau much earlier than in healthy controls. Pharmacologic inhibition of the redox response hinders IL-1β release, confirming the functional link between redox impairment and altered kinetics of secretion. Monocytes from patients with juvenile idiopathic arthritis display normal kinetics of redox response and IL-1β secretion, excluding a role of chronic inflammation in the alterations observed in CAPS. We conclude that preexisting redox alterations distinct from CAPS monocytes anticipate the pathogen-associated molecular pattern molecule-induced generation of the reducing environment favorable to inflammasome activation and IL-1β secretion.antioxidant response | inflammasome | reactive oxygen species | thioredoxin | autoinflammatory diseases

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Section: Discussionsupporting

confidence: 58%

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Tassi¹,

Carta²,

Delfino³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

131

159

View full text Add to dashboard Cite

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“…CIAS1 -associated periodic syndrome patients ( 10,11 ), as well as the involvement of NLRP1 and NLRP3 polymorphisms in the predisposition to several autoimmune disorders ( 5 -8 ), we evaluated the possible association between selected polymorphisms in NALP1 / NLRP1 and CIAS1 / NALP3 / NLRP3 genes and CD in Italian patients. NLRP1 single-nucleotide polymorphisms (SNPs) rs12150220 and rs2670660 were chosen, as they have been previously associated with immune disorders ( 4,5 ).…”

Section: Resultsmentioning

confidence: 99%

The Missense Variation Q705K in CIAS1 / NALP3 / NLRP3 Gene and an NLRP1 Haplotype Are Associated With Celiac Disease

Pontillo

Vendramin

Catamo

et al. 2011

American Journal of Gastroenterology

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“…The clinical characteristics of the study patients are shown in Table 1. The CINCA syndrome patients have been described in part elsewhere (28). Disease onset occurred within the first month of life in most of the study patients.…”

Section: Methodsmentioning

confidence: 99%

Pattern of interleukin‐1β secretion in response to lipopolysaccharide and ATP before and after interleukin‐1 blockade in patients with CIAS1 mutations

Gattorno

Tassi

Carta

et al. 2007

Arthritis & Rheumatism

245

193

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Objective. To examine the synthesis, processing, and secretion of interleukin-1␤ (IL-1␤), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1␤ hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra).Methods. Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1␤ levels were determined by Western blotting and enzyme-linked immunosorbent assay before and after exposure to exogenous ATP.Results. LPS-induced IL-1␤ secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1␤ was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1␤ secretion by the patients' cells in vitro.Conclusion. Our results showed that the requirements of ATP stimulation for IL-1␤ release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1␤ secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1␤.

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Clinical and genetic characterization of Italian patients affected by CINCA syndrome

Cited by 65 publications

References 33 publications

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

The Missense Variation Q705K in CIAS1 / NALP3 / NLRP3 Gene and an NLRP1 Haplotype Are Associated With Celiac Disease

Pattern of interleukin‐1β secretion in response to lipopolysaccharide and ATP before and after interleukin‐1 blockade in patients with CIAS1 mutations

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