Article Dans Une Revue Journal of Experimental Medicine Année : 2024

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

Marion Malphettes

Résumé

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. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients’ T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients’ blood cells revealed typical alterations associated with autoimmunity and all patients presented with 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.

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Immunologie
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Dates et versions

inserm-04879769 , version 1 (10-01-2025)

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Marie Jeanpierre, Jade Cognard, Maud Tusseau, Quentin Riller, Linh-Chi Bui, et al.. Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus. Journal of Experimental Medicine, 2024, 221 (9), pp.e20232337. ⟨10.1084/jem.20232337⟩. ⟨inserm-04879769⟩
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