Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.
Bottom Line: Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-α.In addition, Pep(-/-) mice treated with IFN-α display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-α-treated Pep(+/+) mice.As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-α activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias.
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.Show MeSH
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Mentions: Given the genetic links implicating both IFN-α and PTPN22 in human SLE, we tested whether PEP deficiency may affect the ability of IFN-α to induce SLE. Systemic administration of IFN-α5 (109 PFU/mouse) by adenoviral delivery resulted in 40% mortality in Pep+/+ mice (C57BL/6 background) 2 mo after IFN-α administration (Fig. 1 A). In contrast, IFN-α (109 PFU/mouse) treated Pep−/− mice (C57BL/6) demonstrated 40% mortality by 2 wk and ∼90% mortality by 2 mo. Corresponding with increased mortality, IFN-α5–treated Pep−/− mice developed increased proteinuria, a mild glomerulopathy, antinuclear autoantibodies. and cytopenias when compared to IFN-α5–treated Pep+/+ mice (Fig. 1, B–G). Affected glomeruli of IFN-α5–treated Pep−/− mice have segmental or global thickening of capillary basement membranes and increased mesangial matrix (Fig. 1 D, arrows), resulting in markedly narrowed capillary profiles. Using an arbitrary scoring system (described in Materials and methods), the pathology score for IFN-α5–treated Pep+/+ mice was 0.0 + 0, whereas IFN-α5–treated Pep−/− mice was 0.67 + 0.2 (P = 0.03). Cytopenias, including peripheral neutropenia, anemia, and thrombocytopenia, as well as reductions in splenic neutrophils and monocytes, were also more severe in IFN-α5–treated Pep−/− mice (Fig. 1, E–I). In contrast, whereas IFN-α5 reduced peripheral lymphocytes, there were no differences between IFN-α5–treated Pep+/+ and Pep−/− mice (Fig. 1 J). As IFN-α increased serum BAFF/BLys (Mathian et al., 2005), a key pathogenic factor in SLE, BAFF/BLys levels were elevated in IFN-α5–treated mice compared to LacZ controls, but no differences were observed between IFN-α5–treated Pep+/+ and Pep−/− mice (Fig. 1 K). Together, these data suggest that PEP deficiency accelerates IFN-α5–induced lupus-like disease with increased mortality, proteinuria, glomerulopathy, autoantibody production, and cytopenias.
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.