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
  • 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.