Investigation of Type I Interferon Responses in ANCA-Associated Vasculitis

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (<em>ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L </em>and<em> </em><em>IFIT1</em>) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.I型干扰素（type I interferon，IFN）失调是多种自身免疫性疾病发生的主要致病因素，这类疾病被统称为I型干扰素病（type I interferonopathies），且被认为是此类疾病中慢性炎症的致病关联机制。抗中性粒细胞胞浆抗体（anti-neutrophil cytoplasmic antibody，ANCA）相关血管炎（AAV）是一种以小血管坏死性炎症为特征的自身免疫性疾病。目前AAV的潜在发病机制尚未完全阐明，但多项研究已发现I型干扰素应答存在异常。本研究提出假说：AAV患者体内存在全身性I型干扰素应答失调，符合I型干扰素病的特征。为验证该假说，我们分别检测了AAV患者、健康对照及疾病对照人群的外周血样本中7种干扰素调控基因（interferon regulated genes，IRGs）——ISG15、SIGLEC1、STAT1、RSAD2、IFI27、IFI44L及IFIT1的表达水平，同时检测了其血清样本中3种I型干扰素调控蛋白CXCL10、MCP-1及CCL19的表达水平。结果显示，AAV患者与健康对照的I型干扰素调控基因及蛋白表达水平无显著差异。此外，干扰素调控基因与蛋白的表达水平与AAV患者的临床疾病活动度指标无相关性。综上，本研究认为全身性I型干扰素应答并非AAV发病的关键驱动因素，且AAV不应被归类为I型干扰素病。