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

Nat Immunol. 2012 Dec;13(12):1178-86. doi: 10.1038/ni.2457.

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

Affiliations

Affiliation

1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York, USA.

PMID: 23104095 DOI: 10.1038/ni.2457

Abstract

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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