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Joint Bone Spine. 2018 Nov 22. pii: S1297-319X(18)30426-3. doi: 10.1016/j.jbspin.2018.11.003. [Epub ahead of print]

New data in causes of autoinflammatory diseases.

Author information

1
Service de rhumatologie pédiatrique, CHU de Bicêtre, assistance publique hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France; Université de Paris SUD, 94270 Le Kremlin-Bicêtre, France; Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France. Electronic address: isabelle.kone-paut@aphp.fr.
2
Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France; Sorbonne Universités, 75006 Paris, France; Service de médecine interne, département hospitalo-universitaire inflammation-immunopathologie-biotherapie (DHU i2B), hôpital Tenon, assistance publique-hôpitaux de Paris (AP-HP), 4, rue de la Chine, 75020 Paris, France; Laboratoire Inserm U_933, 75012 Paris, France.
3
Service de rhumatologie pédiatrique, CHU de Bicêtre, assistance publique hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France; Université de Paris SUD, 94270 Le Kremlin-Bicêtre, France; Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France.
4
Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France; Service de pédiatrie générale, Centre hospitalier de Versailles, 179, rue de Versailles, 78150 Le Chesnay, France.
5
Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France; Sorbonne Universités, 75006 Paris, France; Département de médecine interne et immunologie clinique, UMR 7211, département hospitalo-universitaire inflammation-immunopathologie-biotherapie (DHU i2B), assistance publique hôpitaux de Paris (AP-HP), groupe hospitalier Pitié-Salpêtrière, 75005, Paris, France; Inserm, UMR_S 959, 75013 Paris, France; CNRS, FRE3632, 75005 Paris, France.
6
Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France; Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies, Inserm, Université de Montpellier, 34090 Montpellier, France; Département de génétique médicale, maladies rares et médecine personnalisée, CHU de Montpellier, 34295 Montpellier, France.

Abstract

The spectrum of factors known to mediate autoinflammation has broadened recently to include not only interleukin-1 (IL-1) and interferon, but also abnormalities that impair NF-κB pathway negative regulation. The NF-κB pathway is activated upon contact of a ligand with tumor necrosis factor receptor 1 (TNFR1) and plays a pivotal role in triggering the inflammatory process by producing major cytokines such as IL-1, IL-6, and TNF. Negative regulation of the NF-κB pathway, which is essential to stop the inflammatory process, depends on the level of ubiquitination of the proteins associated with TNFR1 and of other intermediate compounds. A20 and otulin are proteins that influence the level of ubiquitination, and a deficiency in either can result in NF-κB activation with overproduction of pro-inflammatory cytokines. Similar to Behçet's disease, A20 haploinsufficiency manifests as oral and genital ulcers and, more rarely, as uveitis. However, transmission is dominant, symptom onset occurs at a younger age, and severe gastrointestinal involvement is at the forefront of the clinical picture. Clinical presentations are extremely diverse. Over their lifetime, affected patients simultaneously or sequentially experience autoinflammatory and autoimmune manifestations. Mild immune deficiency predominantly affecting humoral responses is less common. Otulin deficiency results in systemic inflammatory manifestations at a very young age, with panniculitis, lipodystrophy, and inflammatory bowel disease. The main differential diagnosis is proteasome-associated autoinflammatory syndrome. The treatment of A20 haploinsufficiency and otulin deficiency is challenging and remains unstandardized. The symptoms respond to high-dose glucocorticoid therapy. TNF antagonists and IL-1 antagonists have shown some measure of efficacy.

KEYWORDS:

Autoinflammation; Behcet's disease; HA20; NF; Otulin deficiency; Otulin-related autoinflammatory syndrome; TNFAIP3; Ubiquitination

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