Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease

Abstract

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

Figure 1

a) Schematic representation of STAT3 adapted from. The positions of the 4 different de novo mutations identified in 5 individuals with the polyautoimmune syndrome are shown below the STAT3 domains. The highly conserved sequence at the position of each mutation is provided for various species. b) STAT3 activity of polyautoimmune mutants under (upper) non-stimulated and (lower) IL-6 (20ng/ml) stimulated conditions. The STAT3 reporter activity of 4 polyautoimmune mutants (p.K392R, p.N646K, p.K658N, p.T716M) was examined alongside that of 2 previously described Hyper-IgE mutations (p.R382W, p.V637M) and the wildtype (WT) following transient transfection into HEK293 cells. The dotted line indicates the activity of the WT under either basal (upper) or IL-6 stimulated (lower) conditions. Data are presented as an average fold change relative to WT (n=3) under each experimental condition ±SEM. Typically, IL-6 caused a 20-30-fold increase in activity above basal in cells transfected with WT STAT3.*p<0.05,**p<0.01, ***p<0.001.

Figure 2

Clinical characteristics associated with activating germline STAT3 mutations causing the polyautoimmune syndrome and inactivating germline mutations causing Hyper IgE syndrome.