Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification.
Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification.
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DOI：
10.1136/annrheumdis-2015-208140
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发表时间：
2016-11
影响因子：
27.4
通讯作者：
James JA
中科院分区：
文献类型：
--
作者：
Munroe ME;Lu R;Zhao YD;Fife DA;Robertson JM;Guthridge JM;Niewold TB;Tsokos GC;Keith MP;Harley JB;James JA
系统性红斑狼疮（SLE）的发病机制可能与免疫失调和自身抗体的产生有关，目前尚不清楚。本研究评估了自身抗体、I型干扰素（IFN-α）活性和IFN相关可溶性介质对导致SLE的疾病发展的单独和联合作用。从美国国防部血清储存库获得了在SLE分类前（平均时间跨度= 4.3年）采集的55名个体和与年龄（± 5岁）、性别、种族和样本采集时间匹配的未受影响的健康对照的系列血清样本。评价血清IFN-α活性、IFN相关介质和自身抗体水平，并通过生长曲线建模、路径分析、协方差分析和随机森林模型评估时间关系。在病例组中，自身抗体特异性和IFN相关介质在数年内积累，在疾病分类时达到稳定，而对照组则不然（p<0.001）。在生长曲线模型中，自身抗体阳性与II型IFN失调一致或在II型IFN失调之后，先于IFN-α活性，在SLE分类前不久IFN-α活性和BLyS水平升高（p≤0.005）。采用多变量随机森林模型结合IFN-γ、MCP-3、抗染色质和抗剪接体抗体对病例进行区分（分类前4年的准确率为93%; SLE分类后2年内的准确率为97%）。在SLE分类前数年，II型IFN途径的增强使得自身抗体积累，随后在SLE分类前IFN-α活性升高。在选择免疫过程中的扰动可能有助于识别风险个体，以进行进一步的临床评估或参与前瞻性干预试验。
The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE. Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan = 4.3 years) and unaffected healthy controls matched by age (± 5 years), gender, race, and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators, and autoantibodies were evaluated and temporal relationships assessed by growth curve modeling, path analysis, Analysis of Covariance, and random forest models. In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and BLyS levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, MCP-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% > 4 years pre-classification; 97% within 2 years of SLE classification). Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.