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.
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).
STAT3 is a central member of the JAK/STAT signaling cascade and has long been recognized for its increased transcriptional activity in cancers and autoimmune disorders but has only recently been in the spotlight for its role in the progression of kidney disease.
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in psoriatic skin inflammation and acts as a key player in the pathogenesis and progression of this autoimmune disease.
Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation.
Signal transducer and activator of transcription 3 (STAT3) has a crucial role in various autoimmune disorders including, inflammatory bowel disease (IBD).
Reflecting the requirement of gp130-driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3-dependent, but independent of the cytokine IL-17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity.
Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of opposing STAT1 and STAT3 to have a direct impact on autoimmunity.
AT-rich interactive domain-containing protein 5a (Arid5a) is an RNA-binding protein (RBP) required for autoimmunity via stabilization of interleukin-6 (Il6) and signal transducer and activator of transcription 3 (STAT3) mRNAs.
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.
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.
Calcitriol, the active form of vitamin D, has been shown to decrease STAT1 and STAT3 phosphorylation in cancer cell lines and autoimmune disease mouse models.
These observations suggest that FRA1 and JUNB are associated closely with STAT3 activation, and that this activation leads to Th17 cell differentiation in autoimmune diseases and inflammation.
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.
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.
Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity.
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.
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.