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.
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We thank the children and their families for participating, and F. Iserin, V. Colomb, F. Rüemmele and V. Valayannopoulos for taking care of them. We particularly thank L. Abel, A. Durandy, P. Génin, B. Neven, M. Veron, J.W. Verbsky and R. Weil. H. Walczak (Imperial College London), K. Iwai (Osaka University) and A. Smahi (INSERM U781 Necker hospital, Paris Cité Sorbonne University) provided antibodies and cells. This work was partly funded by US National Center for Advancing Translational Sciences and National Center for Research Resources, US National Institutes of Health (NIH; 8UL1TR000043), St. Giles Foundation, Jeffrey Modell Foundation, Rockefeller University, INSERM, Paris Descartes University, US National Institute of Allergy and Infectious Diseases (R21AI085523; J.-L.C. and D.C.), NIH (5P01AI061093; J.-L.C.), NIH (R01AR050770; V.P.), Canceropole Ile de France (2007; A.I.), European Community Network of Excellence-Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation (LSHC-CT-2005-018683; E.L. and A.I.), Thrasher Research Fund (C. Prando), Institut de Recherches Servier (E.L., F.A. and A.I.) and Manton Foundation (L.D.N.).
The authors declare no competing financial interests.
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Boisson, B., Laplantine, E., Prando, C. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 13, 1178–1186 (2012). https://doi.org/10.1038/ni.2457
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