Signal Transducer and Activation of Transcription 3 (STAT3) is a ubiquitously expressed transcription factor, enriched in immune cells, controlling the expression of target genes involved in proliferation, differentiation, survival and development.
Autosomal Dominant Hyper-IgE syndrome (AD-HIES) is a rare multisystemic condition defined by recurrent skin disease, life-threatening bacterial and fungal infections, and developmental defects. Heterozygous variants in STAT3 have been identified as the most common genetic defect in AD-HIES patients. Since 2007, at least 135 pathogenic variants have been identified, most operating in a dominant negative manner. Carriers present with dysregulated maturation and function of a host of immune cells, such as a reduction in and 17 cells, and an over-active population of 2 cells, leading to disease.
Interestingly, heterozygous gain-of-function (GOF) variants have also been observed, driving a lymphoproliferative immune phenotype characterised by haematological autoimmunity, bronchopulmonary disease and eczema. These patients also present with an impaired cellular immunophenotype, most notably a reduced population of and an enhanced population of cells.
The tight regulation of STAT3 immune signalling is crucial for a robust human immune response. However, LOF and GOF STAT3 signalling do not always culminate in opposing cellular and clinical manifestations. For example, the defect in populations in STAT3 GOF is not mirrored in an increase in populations in STAT3 LOF. Investigating these observations will reveal how balance is achieved and what patient interventions can be implemented with efficacy.
Recently, four novel STAT3 candidate variants have been identified (R31Q, D371Lfs14X, Q333X LOF and F408L GOF). We have biochemically compared these variants through in vitro assays and investigated the cellular immune phenotype and function of the patients’ primary immune cells. This unique approach in comparing LOF and GOF will refine understanding of the complex balancing act of this signalling pathway, allowing improvement in patient treatment and outcome.