PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease.
PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease.
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PhIP-Seq 揭示了间质性肺疾病中的新型自身抗体和独特的内型。
DOI：
10.1101/2023.04.24.538091
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sperling,Anne
中科院分区：
文献类型：
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作者：
Upadhyay,Vaibhav;Yoon,YoungMe;Vazquez,SaraE;Velez,TaniaE;Jones,KirkD;Lee,CathrynT;Law,ChristopherS;Wolters,PaulJ;Lee,Seoyeon;Yang,MonicaM;Farrand,Erica;Noth,Imre;Strek,MaryE;Anderson,Mark;DeRisi,Joseph;Sperling,Anne
间质性肺病(ILDS)是一组异质性疾病，可在结缔组织病(CTD)患者中发展。ILD自身免疫的建立影响预后和治疗。ILD患者通过抗核自身抗体、类风湿因子和其他非特异性试验进行自身免疫筛查。然而，这种方法还没有得到严格的验证，可能会错过自身免疫，这种免疫表现为对ILD中以前没有定义的组织抗原的自身抗体。在这里，我们使用噬菌体免疫沉淀测序(PhIP-Seq)对ILD患者和对照组进行大型、多中心、无偏倚的自身抗体筛选。PhIP-Seq识别了17个新的自身反应靶标，从这些靶标衍生的机器学习分类器区分了ILD血清和对照。在这17个候选者中，我们验证了钙粘素相关家族成员5(CDHR5)作为自身抗原的有效性，并在风湿病患者中发现了CDHR5自身抗体，更重要的是，在以前未被诊断为自身免疫性疾病的受试者中发现了CDHR5自身抗体。CDHR5自身反应性患者的肺组织显示出与核因子κB信号激活和壳三糖苷酶上调一致的转录图谱，壳三糖苷酶是与纤维化相关的分子途径。我们的研究表明，PhIP-Seq在ILD患者中发现了标准临床测试未发现的新型自身抗体。此外，CDHR5自身抗体可能定义了以炎症和纤维化为特征的ILD的一种新的分子内型。
Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NFκB signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.