Abstract
Autoimmune Addison's disease (AAD) is a disorder caused by an immunological attack on the adrenal cortex. The interferon (IFN)-inducible chemokine CXCL10 is elevated in serum of AAD patients, suggesting a peripheral IFN signature. However, CXCL10 can also be induced in adrenocortical cells stimulated with IFNs, cytokines, or microbial components. We therefore investigated whether peripheral blood mononuclear cells (PBMCs) from AAD patients display an enhanced propensity to produce CXCL10 and the related chemokine CXCL9, after stimulation with type I or II IFNs or the IFN inducer poly (I:C). Although serum levels of CXCL10 and CXCL9 were significantly elevated in patients compared with controls, IFN stimulated patient PBMC produced significantly less CXCL10/CXCL9 than control PBMC. Low CXCL10 production was not significantly associated with medication, disease duration, or comorbidities, but the low production of poly (I:C)-induced CXCL10 among patients was associated with an AAD risk allele in the phosphatase nonreceptor type 22 (PTPN22) gene. PBMC levels of total STAT1 and -2, and IFN-induced phosphorylated STAT1 and -2, were not significantly different between patients and controls. We conclude that PBMC from patients with AAD are deficient in their response to IFNs, and that the adrenal cortex itself may be responsible for the increased serum levels of CXCL10.
Highlights
Many patients with autoimmune diseases have signs of a continuous production of type I interferons (IFNs) and display an increased expression of IFN-regulated genes (Ronnblom 2011)
Previous reports have shown that CXCL10 levels are elevated in Autoimmune Addison’s disease (AAD) patients (Rotondi and others 2005; Bratland and others 2013), so we initially determined the serum levels of CXCL10 and CXCL9 in our patient cohort
There were no significant differences in serum levels of CXCL10 or CXCL9 between patients with isolated AAD and patients with autoimmune polyendocrine syndrome type 2 (APS-2), defined as AAD plus additional autoimmune endocrinopathies (Supplementary Fig. S1; Supplementary Data are available online at www.liebertpub.com/jir)
Summary
Many patients with autoimmune diseases have signs of a continuous production of type I interferons (IFNs) and display an increased expression of IFN-regulated genes (Ronnblom 2011). Patients with systemic lupus erythematosus (SLE) have increased serum activity of IFN-a and excessive signatures of interferon-stimulated genes (ISGs) in peripheral blood leukocytes (Blanco and others 2001; Bennett and others 2003). Clinical treatment of infectious or malignant disorders with type I IFNs have been shown to induce autoantibodies and overt autoimmune disease, indicating a role for IFNs in breaking tolerance and promote on-going autoimmune reactions in man (Karlsson-Parra and others 1990). Prospective studies have shown that up to 15% of patients receiving pegylated IFN-a therapy for chronic hepatitis C virus (HCV) infections develop clinical thyroiditis, while 40% develop thyroid autoantibodies (Tomer 2010). The principal type II IFN, IFN-g, is heavily implicated in these disorders as one of the major cytokines produced by antigen-specific autoreactive T cells (Weetman 2004; Arif and others 2014)
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