Pathogenic variants in the NLRP3 LRR domain at position 861 are responsible for a boost-dependent atypical CAPS phenotype.

Antoine Fayand (1, 2) , Margaux Cescato (2) , Laurent Le Corre (2) , Alexandre Terré (1) , Margaux Wacheux (2) , Yixiang Yj. Zhu (2) , Armelle Melet (2) , Thomas Rj. Moreau (2, 3) , Bahram Bodaghi (4) , Fabrice Bonnet (5) , Didier Bronnimann (6) , Laurence Cuisset (7) , Raquel Faria (8) , Gilles Grateau (9) , Pascal Pillet (6) , Catharina Mulders-Manders (10) , Benedicte Neven (11, 12, 13) , Pierre Quartier (14) , Olivier Richer (6) , Léa Savey (9) , Marie-Elise Truchetet (15) , Bénédicte Py (16) , Guilaine Boursier (17) , Jean-Philippe Herbeuval (2) , Sophie Georgin-Lavialle (1, 18) , Mathieu P Rodero (2)

1 CHU Tenon [AP-HP]
2 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
3 Immunologie Translationnelle - Translational Immunology lab
4 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
5 BPH - Bordeaux population health
6 CHU Bordeaux
7 Hôpital Cochin [AP-HP]
8 Universidade do Porto = University of Porto
9 GRC 28 - GRAASU - Groupe de recherche clinique Amylose AA Sorbonne Université
10 Radboud University Medical Center [Nijmegen]
11 Hôpital Necker - Enfants Malades [AP-HP]
12 UPCité - Université Paris Cité
13 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
14 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
15 Hôpital Pellegrin
16 CIRI - Centre International de Recherche en Infectiologie
17 CHU Montpellier
18 SU - Sorbonne Université

Background: Cryopyrin-associated periodic syndrome (CAPS) is associated with NLRP3 pathogenic variants, mostly located in the NACHT domain. Cold induced urticarial rash is one of the main clinical features. We however identified a series of 14 patients with pathogenic variants of the Y861 residue (p.Tyr861) of the LRR domain of NLRP3 and minimal prevalence of cold-induced urticarial rash. Objective: We aimed to address a possible genotype / phenotype correlation for CAPS patients and to investigate at the cellular levels the impact of the Y861C substitution (p.Tyr861Cys) on NLRP3 activation. Methods: Clinical features of 14 CAPS patients with heterozygous substitution at position 861 in the LRR domain of NLRP3 were compared to clinical features of 48 CAPS patients with pathogenic variants outside the LRR domain of NLRP3. IL-1β secretion by PBMCs and purified monocytes from patients and healthy donors was evaluated following LPS and MSU stimulation. Results: Patients with substitution at position 861 of NLRP3 demonstrated a higher prevalence of sensorineural hearing loss while being less prone to skin urticarial. In contrast to classical CAPS patients, cells from patients with a pathogenic variant at position 861 required an activation signal to secrete IL-1β but produced more IL-1β during the early and late phase of secretion than cells from healthy donors. Conclusion: Pathogenic variants of Y861 of NLRP3 drive a boost-dependent over secretion of IL-1β associated with an atypical CAPS phenotype.

Mots clés: NLRP3; CAPS; inflammasome; LRR domain; Interleukin-1; hear loss; deafness; urticaria

Domaines: Immunité innée; Génétique humaine; Immunité adaptative

Antoine Fayand, Margaux Cescato, Laurent Le Corre, Alexandre Terré, Margaux Wacheux, et al.. Pathogenic variants in the NLRP3 LRR domain at position 861 are responsible for a boost-dependent atypical CAPS phenotype.. Journal of Allergy and Clinical Immunology, inPress, ⟨10.1016/j.jaci.2023.07.006⟩. ⟨hal-04182567⟩