Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses
Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses
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DOI：
10.1164/rccm.201203-0506oc
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发表时间：
2013-04-01
影响因子：
24.7
通讯作者：
Duncan, Steven R.
中科院分区：
文献类型：
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作者：
Kahloon, Rehan A.;Xue, Jianmin;Duncan, Steven R.
原理：在大多数特发性肺纤维化（IPF）患者中存在多种自身抗体。我们假设特异性自身抗体可能与IPF的表现有关。目的：确定IPF患者临床相关的抗原特异性免疫反应。方法：采用免疫印迹法和ELISA法检测自身抗体。肺内免疫过程采用免疫组化评价。采用免疫亲和法从血浆中分离到抗热休克蛋白70 (HSP70) IgG。流式细胞术用于白细胞功能研究。测量结果和主要结果：HSP70在发现试验中被确定为潜在的IPF自身抗原。60名对照者中有3%检测到抗hsp70 IgG自身抗体，而横断面IPF队列中有25% (n = 122) (P = 0.0004)，半数IPF患者死亡（P = 0.008）， 70%急性加重（P = 0.0005）。IPF患者的抗hsp70自身抗体与HLA等位基因偏差显著相关，随后FVC降低更大（P = 0.0004）， 1年生存率更低（40 +/- 10% vs 80 +/- 5%；风险比= 4.2；95%置信区间，2.0-8.6;P < 0.0001）。HSP70蛋白、抗原抗体复合物和补体在IPF肺中普遍存在。HSP70蛋白是IPF CD4 T细胞的自身抗原，可诱导淋巴细胞增殖（P = 0.004）和IL-4产生（P = 0.01）。IPF抗hsp70自身抗体激活单核细胞（P = 0.009），增加单核细胞IL-8的产生（P = 0.049）。ELISA证实抗hsp70自身反应性与IPF结果之间存在关联。在其他间质性肺疾病患者中也发现抗hsp70自身抗体，但与临床进展无关。结论：伴有抗hsp70自身抗体的IPF患者近期肺功能恶化和死亡率更高。这些发现表明抗原特异性免疫分析可以为IPF个体患者提供有用的临床信息，并可能对了解IPF的进展有意义。
Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations.Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF.Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies.Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 +/- 10% vs. 80 +/- 5%; hazard ratio = 4.2; 95% confidence interval, 2.0-8.6; P < 0.0001). HSP70 protein, antigen-antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression.Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.