Early-onset autoimmunity associated with SOCS1 haploinsufficiency
Jérôme Hadjadj, Carla N. Castro, Maud Tusseau, Marie‐Claude Stolzenberg, Fabienne Mazerolles, Nathalie Aladjidi, Martin Armstrong, Houman Ashrafian, Ioana Cutcutache, Georg Ebetsberger‐Dachs, Katherine S. Elliott, I. Durieu, Nicole Fabien, Mathieu Fusaro, Maximilian Heeg, Yohan Schmitt, Marc Bras, Julian C. Knight, Jean‐Christophe Lega, Gaëtan Lesca, Anne‐Laure Mathieu, Marion Moreews, Baptiste Moreira, Audrey Nosbaum, Matthew J. Page, Cécile Picard, Timothy Ronan Leahy, Isabelle Rouvet, Ethel Ryan, Damien Sanlaville, Klaus Schwarz, Andrew Skelton, Jean‐François Viallard, Sébastien Viel, Marine Villard, Isabelle Callebaut, Capucine Pïcard, Thierry Walzer, Stephan Ehl, Alain Fischer, Bénédicte Neven, Alexandre Bélot, Frédéric Rieux‐Laucat
Abstract
Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.