Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus: A Comprehensive Analysis of Anticytokine Autoantibodies in Common Rheumatic Diseases.
Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus: A Comprehensive Analysis of Anticytokine Autoantibodies in Common Rheumatic Diseases.
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DOI：
10.1002/art.39607
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Browne SK
中科院分区：
文献类型：
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作者：
Gupta S;Tatouli IP;Rosen LB;Hasni S;Alevizos I;Manna ZG;Rivera J;Jiang C;Siegel RM;Holland SM;Moutsopoulos HM;Browne SK
抗细胞因子自身抗体广泛存在于血液病、肺病和感染性疾病中，然而，对其在自身免疫性疾病中的存在和意义缺乏系统的研究。采用多重微珠检测方法对199例系统性红斑狼疮(SLE)、150例原发性干燥综合征(SS)、149例类风湿性关节炎(RA)和200例健康对照的血清标本进行了24种抗细胞因子自身抗体的检测。为了评价抗细胞因子自身抗体的生物学活性，测定了它们阻断细胞因子诱导的信号转导或蛋白表达的能力。对对照组和SLE患者的全血进行RNA测序。SLE和SS患者对干扰素和干扰素反应性趋化因子干扰素诱导蛋白-10(IP-10)的自身抗体显著过剩。只有抗I型干扰素、白介素12和白介素22的自身抗体具有中和活性。在系统性红斑狼疮中，抗干扰素-γ自身抗体跟踪的疾病活跃度更高，抗双链α/β抗体和干扰素-DNA诱导基因表达增加。相反，阻断抗干扰素-α自身抗体的系统性红斑狼疮患者的I型干扰素基因表达特征正常化。抗III型干扰素(λ2、λ3)和抗IP-10自身抗体是新发现的，还发现了抗巨噬细胞集落刺激因子IL-4、IL-7、IL-17和IL-22的自身抗体，这些抗体在风湿病中尚未发现。抗细胞因子自身抗体与SLE、SS和RA的不同类型相关。抗干扰素自身抗体在SLE和SS中过度表达，并归入不同的功能类别，仅有一部分抗I型干扰素抗体显示中和活性。抗干扰素-γ自身抗体与疾病活动性和干扰素相关基因表达增加相关，提示它们可能在系统性红斑狼疮的发病机制中起作用。
Anticytokine autoantibodies occur across a range of hematologic, pulmonary and infectious diseases, however, systematic investigation of their presence and significance in autoimmune diseases is lacking. Serum samples from patients with systemic lupus erythematosus (SLE) (n=199), primary Sjögren’s syndrome (SS) (n=150), rheumatoid arthritis (RA) (n=149) and healthy controls (n=200) were screened for 24 anticytokine autoantibodies using a multiplex bead-based assay. To evaluate biological activity of anticytokine autoantibodies, their ability to block cytokine-induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in subset of controls and SLE patients. SLE and SS patients had striking excess of autoantibodies against interferons and the interferon-responsive chemokine interferon-inducible-protein-10 (IP-10). Only autoantibodies against type I interferon, interleukin (IL)-12 and IL-22 exhibited neutralizing activity. In SLE, anti-interferon-γ autoantibodies tracked with more disease activity, anti-double-stranded-DNA antibodies, and elevated expression of interferon-α/β-inducible genes. Conversely, SLE patients with blocking anti-interferon-α autoantibodies normalized their type I interferon gene expression signature. Anti-type III interferons (λ2, λ3), and anti-IP-10 autoantibodies were newly recognized and autoantibodies against macrophage-colony stimulating factor, IL-4, IL-7, IL-17 and IL-22, that have not been previously identified in rheumatologic conditions, were discovered. Anticytokine autoantibodies were associated with distinct patterns of SLE, SS and RA. Anti-interferon autoantibodies were overrepresented in SLE and SS and fall into distinct functional classes with only a subset of anti-type I interferon antibodies exhibiting neutralizing activity. Anti-interferon-γ autoantibodies correlated with increased disease activity and interferon-related gene expression, suggesting that they may contribute to the pathogenesis of SLE.