Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

STAT3 gain-of-function syndrome

“…Biopsies typically show lymphoid reactive hyperplasia. Malignancy is uncommon, but has been described in a small number of patients including marginal zone B cell lymphoma, large granular lymphocytic leukemia, and non-Hodgkin's lymphoma, suggesting an increased risk in this disease given the relatively small number of patients (3)(4)(5).…”

“…Gain-of-function (GOF) variants in STAT3 , encoding signal transducer and activator of transcription 3 (STAT3), lead to a syndrome of early-onset autoimmunity with immune dysregulation first recognized in 2014 ( 3 ). Since the initial discovery of the molecular mechanism of STAT3 GOF syndrome, further identification and investigation of these patients has increased understanding of the often severe clinical consequences of this disease and the effects of abnormal STAT3 regulation on immunity, and provided rationale for targeted therapeutic approaches ( 4 ). Here we review our current knowledge of the mechanisms and clinical course of this immune dysregulation syndrome.…”

“…Much attention has been given to the CD4+ T cell populations in STAT3 GOF patients due to the known role of IL-6 signaling in T regulatory and Th17 cell development and the phenotypic connection of the patients with others that carry T regulatory cell defects ( 14 ). Enhanced STAT3 signaling would be predicted to result in elevated CD4+ Th17 cells ( 22 ), however, while it is clear that patients with STAT3-hyper-IgE-syndrome due to dominant negative STAT3 loss-of-function variants have decreased CD4+ Th17 cells ( 23 ), it remains unclear if the corollary of enhanced Th17 cells is present in STAT3 GOF patients ( 4 ). This may be secondary to the treatment status of patients at the time of immune profiling, as immune modulation can impact the differentiation of CD4+ T cells ( 24 ).…”

“…This may be secondary to the treatment status of patients at the time of immune profiling, as immune modulation can impact the differentiation of CD4+ T cells ( 24 ). When enumerated, CD4+ T regulatory cells have been noted to be decreased in STAT3 GOF patients ( 4 , 5 , 9 , 16 , 20 , 25 , 26 ), which may also have decreased function ( 10 ). However, recently, a murine model for STAT3 GOF generated through CRISPR/Cas9 genetic engineering in a diabetic prone mouse model showed that disease can be driven by a cell intrinsic defect in CD8+ T cells which do not progress through to terminal exhaustion and then drive pathology ( 27 ).…”

“…The original clinical descriptions of patients with STAT3 GOF included early onset type I diabetes mellitus, post-natal growth failure, and lymphoproliferation ( 3 , 5 , 10 ). Although all 3 remain hallmark symptoms of the disease, the clinical and immune phenotype has significantly expanded as additional patients have been identified ( 4 ) ( Figure 2 ). Onset of disease is early, occurring at a median of 2.3 years ( 4 , 14 ).…”