Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

Bertrand Boisson (1) , Emmanuel Laplantine (2) , Carolina Prando (1) , Silvia Giliani (3) , Elisabeth Israelsson (4) , Zhaohui Xu (5) , Avinash Abhyankar (1) , Laura Israël (6) , Giraldina Trevejo-Nunez (1) , Dusan Bogunovic (1) , Alma-Martina Cepika (5) , Donna Macduff (7) , Maya Chrabieh (6) , Marjorie Hubeau (6) , Fanny Bajolle (8) , Marianne Debré (8) , Evelina Mazzolari (3) , Donatella Vairo (3) , Fabrice Agou (9) , Herbert W Virgin (7) , Xavier Bossuyt (10) , Caroline Rambaud (11) , Fabio Facchetti (3) , Damien Bonnet (12, 8) , Pierre Quartier (12, 8) , Jean-Christophe Fournet (12, 8) , Virginia Pascual (5) , Damien Chaussabel (4, 5) , Luigi Notarangelo (13) , Anne Puel (6) , Alain Israël (2) , Jean-Laurent Casanova (1, 6, 8) , Capucine Picard (6, 8)

1 Rockefeller University [New York]
2 SMAC - Signalisation Moléculaire et Activation Cellulaire
3 UniBs - Università degli Studi di Brescia = University of Brescia
4 BRI - Benaroya Research Institute [Seattle]
5 BIIR - Baylor Institute for Immunology Research
6 Inserm U980 - Génétique Humaine des Maladies Infectieuses
7 Washington University School of Medicine in St. Louis
8 CHU Necker - Enfants Malades [AP-HP]
9 Biochimie Structurale et Cellulaire
10 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
11 Hôpital Raymond Poincaré [AP-HP]
12 UPD5 - Université Paris Descartes - Paris 5
13 HMS - Harvard Medical School [Boston]

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1β (IL-1β) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB–dependent IL-1β responses differently in different cell types.

Domains: Life Sciences [q-bio]

Bertrand Boisson, Emmanuel Laplantine, Carolina Prando, Silvia Giliani, Elisabeth Israelsson, et al.. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nature Immunology, 2012, 13 (12), pp.1178-1186. ⟨10.1038/ni.2457⟩. ⟨pasteur-03277102⟩