Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies.
Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies.
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先天和自适应血清介质的失调前面是全身性红斑狼疮分类，并提高自身抗体的预后准确性。
DOI：
10.1016/j.jaut.2016.06.001
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发表时间：
2016-11
影响因子：
12.8
通讯作者：
James JA
中科院分区：
文献类型：
--
作者：
Lu R;Munroe ME;Guthridge JM;Bean KM;Fife DA;Chen H;Slight-Webb SR;Keith MP;Harley JB;James JA
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，临床前阶段的免疫失调和症状积累知之甚少。抗核自身抗体（ANA）特异性的积累是即将发生的临床疾病的标志。然而，许多ANA阳性个体仍然健康，这表明SLE发病机制的基础是额外的免疫失调。事实上，我们最近已经证明，干扰素（IFN）途径失调，在临床前SLE。为了确定其他形式的免疫失调是否有助于临床前SLE发病机制，我们测量了SLE分类前收集的84例患者样本中的SLE相关自身抗体和可溶性介质（平均时间跨度= 5.98年），并与未受影响的健康对照样本进行了比较，这些样本与种族，性别，年龄（± 5岁）和样本采集时间相匹配。我们发现，在自身抗体阳性之前或同时，与对照组相比，多个可溶性介质，包括白细胞介素（IL）-5，IL-6和IFN-γ，在病例中显著升高超过3.5年分类前。其他介质，包括先天性细胞因子，IFN相关趋化因子，可溶性肿瘤坏死因子（TNF）超家族介质增加纵向接近SLE分类的情况下，但在控制。特别是，B淋巴细胞刺激因子（BLyS）和增殖诱导配体（APRIL）的水平在病例和对照组中相当，直到分类前不到10个月。在整个预分类期间，将ANA和抗Ro/SSA阳性与IL-5、IL-6和IFN-γ诱导的趋化因子IFN-γ水平结合的随机森林模型以92%（± 1.8%）的准确度区分未来的SLE患者，相比之下，仅使用ANA阳性的准确度为78%。这些数据表明，涉及多个途径的免疫失调有助于SLE发病机制。重要的是，不同的免疫学特征可预测将发展为临床SLE的个体，并可用于描绘早期发病机制，发现治疗靶点和设计预防试验。
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a poorly understood preclinical stage of immune dysregulation and symptom accrual. Accumulation of antinuclear autoantibody (ANA) specificities is a hallmark of impending clinical disease. Yet, many ANA-positive individuals remain healthy, suggesting that additional immune dysregulation underlies SLE pathogenesis. Indeed, we have recently demonstrated that interferon (IFN) pathways are dysregulated in preclinical SLE. To determine if other forms of immune dysregulation contribute to preclinical SLE pathogenesis, we measured SLE-associated autoantibodies and soluble mediators in samples from 84 individuals collected prior to SLE classification (average timespan = 5.98 years), compared to unaffected, healthy control samples matched by race, gender, age (± 5 years), and time of sample procurement. We found that multiple soluble mediators, including interleukin (IL)-5, IL-6, and IFN-γ, were significantly elevated in cases compared to controls more than 3.5 years pre-classification, prior to or concurrent with autoantibody positivity. Additional mediators, including innate cytokines, IFN-associated chemokines, and soluble tumor necrosis factor (TNF) superfamily mediators increased longitudinally in cases approaching SLE classification, but not in controls. In particular, levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were comparable in cases and controls until less than 10 months pre-classification. Over the entire pre-classification period, random forest models incorporating ANA and anti-Ro/SSA positivity with levels of IL-5, IL-6, and the IFN-γ-induced chemokine, MIG, distinguished future SLE patients with 92% (± 1.8%) accuracy, compared to 78% accuracy utilizing ANA positivity alone. These data suggest that immune dysregulation involving multiple pathways contributes to SLE pathogenesis. Importantly, distinct immunological profiles are predictive for individuals who will develop clinical SLE and may be useful for delineating early pathogenesis, discovering therapeutic targets, and designing prevention trials.
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影响因子：
2.2
作者：
Dossus, Laure;Becker, Susen;Rinaldi, Sabina
通讯作者：
Rinaldi, Sabina
影响因子：
--
作者：
Deane, Kevin D.;Striebich, Christopher C.;Goldstein, Barbara L.;Derber, Lezlie A.;Parish, Mark C.;Feser, Marie L.;Hamburger, Elaine M.;Brake, Stacey;Belz, Cindy;Goddard, James;Norris, Jill M.;Karlson, Elizabeth W.;Holers, V. Michael
通讯作者：
Holers, V. Michael
影响因子：
5.1
作者：
Genuer, Robin;Poggi, Jean-Michel;Tuleau-Malot, Christine
通讯作者：
Tuleau-Malot, Christine
影响因子：
158.5
作者：
Arbuckle, MR;McClain, MT;Harley, JB
通讯作者：
Harley, JB
影响因子：
8.7
作者：
Clancy RM;Markham AJ;Buyon JP
通讯作者：
Buyon JP