Pulmonary sarcoidosis is associated with exosomal vitamin D-binding protein and inflammatory molecules

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Martinez-Bravo, Maria-Jose^1,2  Wahlund, Casper J. E.^1,2  Qazi, Khaleda Rahman^1,2  Moulder, Robert³  Lukic, Ana⁴  Radmark, Olof⁴  Lahesmaa, Riitta³  Grunewald, Johan^5,6  Eklund, Anders^5,6  Gabrielsson, Susanne^1,2 

[1] Karolinska Inst, Unit Immunol & Allergy, Stockholm, Sweden

[2] Karolinska Univ Hosp, L2 04, SE-17176 Stockholm, Sweden

[3] Univ Turku, Turku Ctr Biotechnol, SF-20500 Turku, Finland

[4] Univ Hosp, Karolinska Inst, Div Physiol Chem 2, Dept Med Biochem & Biophys, Solna, Sweden

[5] Karolinska Inst, Resp Unit, Stockholm, Sweden

[6] Univ Hosp, Stockholm, Sweden

关键词: Exosomes;    extracellular vesicles;    sarcoidosis;    leukotrienes;    vitamin D-binding protein;    proteome;    biomarkers;    complement;   

DOI  :  10.1016/j.jaci.2016.05.051

来源: Elsevier

【 摘 要 】

Background: Sarcoidosis is an inflammatory granulomatous disorder characterized by accumulation of T(H)1-type CD4(+) T cells and immune effector cells within affected organs, most frequently the lungs. Exosomes are extracellular vesicles conveying intercellular communication with possible diagnostic and therapeutic applications. Objectives: We aimed to provide an understanding of the proinflammatory role of bronchoalveolar lavage fluid (BALF) exosomes in patients with sarcoidosis and to find candidates for disease biomarkers. Methods: We performed a mass spectrometric proteomics characterization of BALF exosomes from 15 patients with sarcoidosis and 5 healthy control subjects and verified the most interesting results with flow cytometry, ELISA, and Western blot analyses in an additional 39 patients and 22 control subjects. Results: More than 690 proteins were identified in the BALF exosomes, several of which displayed significant upregulation in patients, including inflammation-associated proteins, such as leukotriene A(4) hydrolase. Most of the complement-activating factors were upregulated, whereas the complement regulator CD55 was seen less in patients compared with healthy control subjects. In addition, for the first time, we detected vitamin D-binding protein in BALF exosomes, which was more abundant in patients. To evaluate exosome-associated vitamin D-binding protein as a biomarker for sarcoidosis, we investigated plasma exosomes from 23 patients and 11 healthy control subjects and found significantly higher expression in patients. Conclusion: Together, these data contribute to understanding the role of exosomes in lung disease and provide suggestions for highly warranted sarcoidosis biomarkers. Furthermore, the validation of an exosome-associated biomarker in the blood of patients provides novel, and less invasive, opportunities for disease diagnosis.

【 授权许可】

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