Haploinsufficiency in PTPN2 leads to early onset systemic autoimmunity from Evans syndrome to lupus

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways downstream of several cytokine pathways. All identified mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro cytokine reporter and phosphatase assays, and by hyperproliferation of patients’ T cells stimulated with cytokines. Furthermore, patients exhibited high serum levels of various inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in various STAT factors. Flow cytometry analysis of patients’ blood cells revealed typical alterations associated with autoimmunity, such as an expansion of CD11c+ B cells and follicular helper T cells, and all patients presented with anti-platelet or other autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.