Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, USA.
Arthritis Res Ther. 2019 Apr 29;21(1):107. doi: 10.1186/s13075-019-1878-y.
BACKGROUND AND AIM: Interferons (IFNs) are considered to be key molecules in the pathogenesis of systemic lupus erythematosus (SLE). We measured levels of type I, II and III IFNs in a large cohort of patients with systemic lupus erythematosus (SLE) and controls and explored associations among high levels of different IFN types and distinct SLE features. METHODS: Four hundred ninety-seven well-characterized SLE patients and 322 population controls were included. Disease activity was assessed by SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM). Functional type I IFN activity was estimated by a WISH reporter cell assay. Levels of IFN-γ were estimated by MSD 30-plex assay. IFN-α and IFN-λ1 were measured by ELISA. Values above the third quartile of patients' measurements were defined as high. Associations among high IFN results and SLE features were investigated by nominal regression analysis. RESULTS: All IFN measurements were higher in SLE patients than in controls. High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations. Specific SLE subsets were linked to the upregulation of different subtypes of circulating IFNs: high IFN-γ to arthritis, nephritis and anti-Ro60 antibodies and high IFN-α to mucocutaneous engagement and anti-Ro52 and anti-La antibodies. Isolated high IFN-λ1 was coupled to anti-nucleosome antibodies and less severe SLE. CONCLUSIONS: High functional type I IFN activity captures active SLE in most domains, but more distinct patterns of organ involvement are associated with profiles of circulating IFNs. High IFN-γ as well as high functional type I IFN activity is a characteristic of severe SLE with nephritis and arthritis, while elevated levels of IFN-α associate with active mucocutaneous inflammation and a more benign cardiovascular profile. IFN-λ1 in isolation is associated with milder disease. Our findings suggest that IFNs contribute to the heterogeneity of clinical manifestations in SLE, and measuring circulating IFNs could assist in designing clinical trials with therapies targeting IFN pathways.
背景与目的：干扰素（IFNs）被认为是系统性红斑狼疮（SLE）发病机制中的关键分子。我们在一大群系统性红斑狼疮（SLE）患者和对照者中测量了 I、II 和 III 型 IFNs 的水平，并探讨了不同 IFN 类型的高水平与 SLE 特征之间的关系。
方法：纳入 497 名特征明确的 SLE 患者和 322 名人群对照者。疾病活动度通过 SLE 疾病活动指数（SLEDAI）和系统性红斑狼疮活动度测量（SLAM）评估。通过 WISH 报告细胞测定估计功能性 I 型 IFN 活性。IFN-γ 水平通过 MSD 30-plex 测定估计。IFN-α 和 IFN-λ1 通过 ELISA 测量。将患者测量值的第三四分位数以上的值定义为高值。通过名义回归分析研究高 IFN 结果与 SLE 特征之间的关系。
结果：SLE 患者的所有 IFN 测量值均高于对照组。高 I 型 IFN 活性与 IFN-γ 和 IFN-α 水平相关，并且与大多数疾病领域的活动性 SLE 相关：体重减轻、疲劳、发热、皮疹、淋巴结病、关节炎、肾炎和血液学表现。特定的 SLE 亚群与循环 IFNs 的不同亚型上调相关：高 IFN-γ 与关节炎、肾炎和抗 Ro60 抗体相关，高 IFN-α 与黏膜皮肤受累和抗 Ro52 和抗 La 抗体相关。孤立的高 IFN-λ1 与抗核小体抗体相关，且 SLE 较轻。
结论：高功能性 I 型 IFN 活性在大多数疾病领域中捕获活动性 SLE，但与循环 IFNs 相关的更独特的器官受累模式与更具特征性。高 IFN-γ 以及高功能性 I 型 IFN 活性是伴有肾炎和关节炎的严重 SLE 的特征，而 IFN-α 水平升高与活跃的黏膜皮肤炎症和更良性的心血管特征相关。孤立的 IFN-λ1 与较轻的疾病相关。我们的发现表明 IFNs 有助于 SLE 临床表现的异质性，并且测量循环 IFNs 可以帮助设计针对 IFN 途径的治疗方法的临床试验。
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