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Nature Research, Nature Immunology, 12(13), p. 1178-1186, 2012

DOI: 10.1038/ni.2457

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

Journal article published in 2012 by Bertrand Boisson, 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 and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.