ESPE Abstracts (2016) 86 S4.1

Activating Mutations in STAT3 Leading to Early-Onset Multi-organ Autoimmune Disease

Megan Cooper


MO, USA


Background: Monogenic disorders of the immune system are increasingly recognized as a cause of early-onset immune dysregulation and autoimmunity. We recently identified 13 patients with a newly-described syndrome of early-onset polyautoimmunity, including endocrinopathies, and immune deficiency caused by gain-of-function (GOF) variants in the STAT3 gene. STAT3 is a highly conserved transcription factor that affects cytokine-induced changes in gene expression. Patients bearing germline, loss-of-function STAT3 variants suffer from recurrent infections. Somatic, gain-of-function (GOF) mutations in STAT3 are associated with cancers. The identification of early-onset autoimmunity caused by germline STAT3 GOF variants thus represents a third category of disease caused by alterations in STAT3.

Objective and hypotheses: The objectives of this talk are to discuss this recently identified syndrome of STAT3 GOF including review of clinical and immunological features of this disorder, potential mechanisms of disease, and therapeutic strategies.

Method: There have been more than 20 patients reported with autoimmunity associated with GOF STAT3. I will review the clinical features of these patients and recent work from our laboratory investigating the mechanism of immune dysregulation due to STAT3 GOF.

Results: Patients with STAT3 GOF present at a young age (average 4 years), usually with autoimmunity of two or more organ systems. Cytopenias are the most common autoimmune disease, and others include type I DM (including neonatal onset), enteropathy, lung disease, thyroid disease, and arthritis. The majority of STAT3 GOF patients have short stature, for unclear reasons but possibly due to impaired STAT5b signaling. Analysis of T cell populations shows decreased peripheral blood regulatory T cells (Tregs). Recent studies from our laboratory suggest impaired Treg differentiation and enhanced Th17 differentiation directly caused by STAT3 GOF variants. Therapies have included immune suppression, stem cell transplantation, and anti-IL-6R.

Conclusion: STAT3 GOF is a cause of early-onset autoimmunity. While the cause of immune dysregulation has not been fully elucidated, there are indications that dysregulation of T cell differentiation may contribute to disease.

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