Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation.
Activating heterozygous germline mutations in the signal transducer and activator of transcription 3 (<i>STAT3</i>) gene are associated with the rare autoimmune disorderautoimmune disease, multisystem, infantile onset (ADMIO).
The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases.
Patients with germline STAT3 GOF mutations have an increased frequency of early-onset multiorgan autoimmunity (i.e. autoimmune enteropathy, type 1 diabetes mellitus, autoimmune interstitial lung disease and autoimmune cytopenias), lymphoproliferation, short stature and, less frequently, severe recurrent infections.
Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) polymorphisms have been demonstrated as a common risk factor for a number of autoimmune diseases.
Interleukin-23 receptor (IL-23R) and signal transducer and activator of transcription 3 (STAT3) polymorphisms are common risk factors for a number of T helper (Th) 17-mediated autoimmune diseases.
Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity.
This case sheds light on the emerging role of signal transducer and activator of transcription 3 gain-of-function mutation in the pathogenesis of autoimmune diseases, and further addresses the therapeutic role of interleukin-6 blocker treatment in this syndrome.
Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3.
Janus kinase 1 (JAK1), JAK2, and signal transducer and activator of transcription 3 (STAT3) play an important role in Th1 and Th17 differentiation and gene polymorphisms of these factors have been demonstrated to be associated with certain autoimmune diseases.
These results show STAT3 and NF-<i>κ</i>B as two important and complementary regulators of the tolerogenic behaviour of DCs, which should be considered as molecular targets in the design of DC-based suppressive immunotherapies for the treatment of autoimmune disorders.
Job's (hyper IgE) syndrome or inflammatory bowel disease (IBD) have now established a clear-cut role for the IL-10/STAT3 axis in immune tolerance; further understanding of these processes could lead to novel therapeutic approaches for autoimmune diseases.
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.
The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3).
However, because IFN-α is thought to elicit its therapeutic effect via enhancement of an antitumor immune response mediated by lymphocytes that can be activated by IFN-α administrations, it is probable that the suppression of STAT3 in vivo relates to autoimmune disorders.
Signal transducer and activator of transcription 3 (STAT3) has a crucial role in various autoimmune disorders including, inflammatory bowel disease (IBD).
Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.