RNF213-associated urticarial lesions with hypercytokinemia.
J Allergy Clin Immunol
; 150(6): 1545-1555, 2022 12.
Article
en En
| MEDLINE
| ID: mdl-35780935
ABSTRACT
BACKGROUND:
Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic autoinflammatory diseases.OBJECTIVE:
We sought to investigate a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia.METHODS:
We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling, and transcriptomic analyses on samples from 2 patients. The identified candidate protein was studied after in vitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was used to unveil the associated protein network.RESULTS:
The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of proinflammatory (IL-1ß, IL-6, and TNF-α) and anti-inflammatory (IL-10 and IL-1 receptor antagonist [IL-1RA]) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever, and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. The affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein with a poorly known physiologic role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213.CONCLUSION:
We identified a new entity characterized by chronic urticarial lesions associated with a clinically blunted hypercytokinemia. This disease, which is due to loss of function of RNF213, reveals mysterin's key role in the complex molecular network of innate immunity.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteómica
/
Síndrome de Liberación de Citoquinas
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Francia