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Neutrophil extracellular traps may contribute to interstitial lung disease associated with anti-MDA5 autoantibody positive dermatomyositis

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Abstract

In dermatomyositis (DM), anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody (autoAb) marks a subtype with low grade or absent muscle inflammation but frequent and rapidly progressive interstitial lung disease (ILD). The pathogenesis of ILD remains poorly unknown. The aim of the study is to explore whether neutrophil extracellular traps (NETs) are involved in the development of ILD in DM patients with anti-MDA5 autoAb. Patients with clinically amyopathic dermatomyositis (CADM, n = 20), classic dermatomyositis (cDM, n = 30), polymyositis (PM, n = 20), and healthy controls (HC, n = 20) were enrolled. Anti-MDA5 autoantibody and Krebs von den Lungen-6 (KL-6) were detected by ELISA. Circulating levels of NETs were assessed by the quantification of both serum cell-free DNA (cfDNA) and LL-37 (cathelicidin LL-37). Immunofluorescent staining was used to visualize NETs ex vivo. The elevated circulating NETs level was detected in DM patients with ILD complication. Compared to anti-MDA5 Ab− DM patients, anti-MDA5 Ab+ DM patients had the higher concentrations of serum cfDNA (293 ± 69 vs 252 ± 63 ng/ml; P = 0.035) and serum LL-37 (0.6 ± 1.0 vs 0.2 ± 0.2 ng/ml; P = 0.026). Positive correlations were established between serum levels of cfDNA and KL-6 in DM patients (r s = 0.4422, P = 0.0003). anti-MDA5 Ab+ sera, other than anti-MDA5 Ab− sera, could induce greater numbers of normal neutrophils to form NETs in vitro. These data suggest that aberrant NETs formation may be involved in the pathogenesis of ILD in DM patients with anti-MDA5 autoAb.

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References

  1. Sontheimer RD (2002) Would a new name hasten the acceptance of amyopathic dermatomyositis (dermatomyositis siné myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness. J Am Acad Dermatol 46(4):626–636

    Article  PubMed  Google Scholar 

  2. Gerami P, Schope JM, McDonald L, Walling HW, Sontheimer RD (2006) A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol 54(4):597–613

    Article  PubMed  Google Scholar 

  3. Sato S, Kuwana M (2010) Clinically amyopathic dermatomyositis. Curr Opin Rheumatol 22(6):639–643

    Article  PubMed  Google Scholar 

  4. Sato S, Hirakata M, Kuwana M, Suwa A, Inada S, Mimori T, Nishikawa T, Oddis CV, Ikeda Y (2005) Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum 52(5):1571–1576

    Article  CAS  PubMed  Google Scholar 

  5. Mimori T, Nakashima R, Hosono Y (2012) Interstitial lung disease in myositis: clinical subsets, biomarkers, and treatment. Curr Rheumatol Rep 14(3):264–274

    Article  CAS  PubMed  Google Scholar 

  6. Sato S, Hoshino K, Satoh T, Fujita T, Kawakami Y, Fujita T, Kuwana M (2009) RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum 60(7):2193–2200

    Article  CAS  PubMed  Google Scholar 

  7. Koga T, Fujikawa K, Horai Y, Okada A, Kawashiri SY, Iwamoto N, Suzuki T, Nakashima Y, Tamai M, Arima K, Yamasaki S, Nakamura H, Origuchi T, Hamaguchi Y, Fujimoto M, Ishimatsu Y, Mukae H, Kuwana M, Kohno S, Eguchi K, Aoyagi K, Kawakami A (2012) The diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM. Rheumatology (Oxford) 51(7):1278–1284

    Article  CAS  Google Scholar 

  8. Chen Z, Cao M, Plana MN, Liang J, Cai H, Kuwana M, Sun L (2013) Utility of anti-melanoma differentiation-associated gene 5 antibody measurement in identifying patients with dermatomyositis and a high risk for developing rapidly progressive interstitial lung disease: a review of the literature and a meta-analysis. Arthritis Care Res (Hoboken) 65(8):1316–1324

    Article  CAS  Google Scholar 

  9. Thieblemont N, Wright HL, Edwards SW, Witko-Sarsat V (2016) Human neutrophils in auto-immunity. Semin Immunol 28(2):159–173

    Article  CAS  PubMed  Google Scholar 

  10. Kahlenberg JM, Kaplan MJ (2013) Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol 191(10):4895–4901

    Article  CAS  PubMed  Google Scholar 

  11. Marie I, Hachulla E, Cherin P, Dominique S, Hatron PY, Hellot MF, Devulder B, Herson S, Levesque H, Courtois H (2002) Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 47(6):614–622

    Article  CAS  PubMed  Google Scholar 

  12. Schnabel A, Reuter M, Biederer J, Richter C, Gross WL (2003) Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment. Semin Arthritis Rheum 32(5):273–284

    Article  PubMed  Google Scholar 

  13. Zhang S, Shu X, Tian X, Chen F, Lu X, Wang G (2014) Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications. Clin Exp Immunol 177(1):134–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bohan A, Peter JB (1975) Polymyositis and dermatomyositis (first of two parts). N Engl J Med 292(7):344–347

    Article  CAS  PubMed  Google Scholar 

  15. Bohan A, Peter JB (1975) Polymyositis and dermatomyositis (second of two parts). N Engl J Med 292(8):403–407

    Article  CAS  PubMed  Google Scholar 

  16. Society AT (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161(2 Pt 1):646–664

    Google Scholar 

  17. Chen F, Wang D, Shu X, Nakashima R, Wang G (2012) Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol Int 32(12):3909–3915

    Article  CAS  PubMed  Google Scholar 

  18. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ, Banchereau J, Pascual V (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl med 3(73):73ra20

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang H, Li T, Chen S, Gu Y, Ye S (2015) Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol 67(12):3190–3200

    Article  CAS  PubMed  Google Scholar 

  20. Lögters T, Paunel-Görgülü A, Zilkens C, Altrichter J, Scholz M, Thelen S, Krauspe R, Margraf S, Jeri T, Windolf J, Jager M (2009) Diagnostic accuracy of neutrophil-derived circulating free DNA (cf-DNA/NETs) for septic arthritis. J Orthop Res 27(11):1401–1407

    Article  PubMed  Google Scholar 

  21. Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T, Kondo T, Kawabata H, Kadowaki N, Takaori-Kondo A (2013) Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 19(12):1683–1689

    Article  CAS  PubMed  Google Scholar 

  22. Wang H, Sha LL, Ma TT, Zhang LX, Chen M, Zhao MH (2016) Circulating level of neutrophil extracellular traps is not a useful biomarker for assessing disease activity in antineutrophil cytoplasmic antibody-associated vasculitis. PLoS One 11(2):e0148197

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kohno N, Akiyama M, Kyoizumi S, Hakoda M, Kobuke K, Yamakido M (1988) Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma. Jpn J Clin Oncol 18(3):203–216

    CAS  PubMed  Google Scholar 

  24. Yamakawa H, Hagiwara E, Kitamura H, Yamanaka Y, Ikeda S, Sekine A, Baba T, Okudela K, Iwasawa T, Takemura T, Kuwano K, Ogura T (2017) Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease. J Thorac Dis 9(2):362–371

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bandoh S, Fujita J, Ohtsuki Y, Ueda Y, Hojo S, Tokuda M, Dobashi H, Kurata N, Yoshinouchi T, Kohno N, Takahara J (2000) Sequential changes of KL-6 in sera of patients with interstitial pneumonia associated with polymyositis/dermatomyositis. Ann Rheum Dis 59(4):257–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Labrador-Horrillo M, Martinez MA, Selva-O’Callaghan A, Trallero-Araguas E, Balada E, Vilardell-Tarres M, Juarez C (2014) Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis. J Immunol Res 2014:290797

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ceribelli A, Fredi M, Taraborelli M, Cavazzana I, Tincani A, Selmi C, Chan JY, Chan EK, Satoh M, Franceschini F (2014) Prevalence and clinical significance of anti-MDA5 antibodies in European patients with polymyositis/dermatomyositis. Clin Exp Rheumatol 32(6):891–897

    PubMed  Google Scholar 

  28. Gono T, Kawaguchi Y, Satoh T, Katsumata Y, Takagi K, Masuda I, Tochimoto A, Baba S, Okamoto Y, Ota Y, Yamanaka H (2010) Clinical manifestation and prognostic factor in anti-melanoma differentiation-associated gene 5 antibody-associated interstitial lung disease as a complication of dermatomyositis. Rheumatology (Oxford) 49(9):1713–1719

    Article  CAS  Google Scholar 

  29. Ikeda S, Arita M, Morita M, Ikeo S, Ito A, Tokioka F, Noyama M, Misaki K, Notohara K, Ishida T (2015) Interstitial lung disease in clinically amyopathic dermatomyositis with and without anti-MDA-5 antibody: to lump or split. BMC Pulm Med 15:159

    Article  PubMed  PubMed Central  Google Scholar 

  30. Sakurai N, Nagai K, Tsutsumi H, Ichimiya S (2011) Anti-CADM-140 antibody-positive juvenile dermatomyositis with rapidly progressive interstitial lung disease and cardiac involvement. J Rheumatol 38(5):963–964

    Article  PubMed  Google Scholar 

  31. Miyake M, Sakai A, Nishijima C, Kita T, Nitta E, Kawashima A, Hamaguchi Y, Fujimoto M, Inaoki M (2014) Detection of anti-CADM-140/MDA5 antibodies in a patient with classic dermatomyositis developing rapidly progressive interstitial lung disease. J Dermatol 41(7):664–665

    Article  PubMed  Google Scholar 

  32. Cheng OZ, Palaniyar N (2013) NET balancing: a problem in inflammatory lung diseases. Front Immunol 4:1

    PubMed  PubMed Central  Google Scholar 

  33. Müller-Redetzky H (2015) Targeting neutrophil extracellular traps in acute lung injury: a novel therapeutic approach in acute respiratory distress syndrome. Anesthesiology 122(4):725–727

    Article  PubMed  Google Scholar 

  34. Lu X, Tang Q, Lindh M, Dastmalchi M, Alexanderson H, Popovic Silwerfeldt K, Agerberth B, Lundberg IE, Wick C (2017) The host defense peptide LL-37 a possible inducer of the type I interferon system in patients with polymyositis and dermatomyositis. J Autoimmun 78:46–56

    Article  CAS  PubMed  Google Scholar 

  35. Kessenbrock K, Krumbholz M, Schönermarck U, Back W, Gross WL, Werb Z, Grone HJ, Brinkmann V, Jenne DE (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 15(6):623–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V, Thompson P, Chen P, Fox DA, Pennathur S, Kaplan MJ (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5(178):178ra140

    Article  Google Scholar 

  37. Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, Cosmi L, Lunardi C, Annunziato F, Romagnani S, Cassatella MA (2010) Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 115(2):335–343

    Article  CAS  PubMed  Google Scholar 

  38. Swiecki M, McCartney SA, Wang Y, Colonna M (2011) TLR7/9 versus TLR3/MDA5 signaling during virus infections and diabetes. J Leukoc Biol 90(4):691–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81172870).

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Authors and Affiliations

  1. Department of Rheumatology, West China Hospital, Sichuan University, No.37 Guoxue Lane, Chengdu, 610041, China

    Yun Peng, Suhan Zhang, Yi Zhao, Yi Liu & Bing Yan

  2. Department of Rheumatology, The First Affiliated Hospital of Xiamen University, No.55 Zhenhai Road, Xiamen, 361000, China

    Yun Peng

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Correspondence to Bing Yan.

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Ethical approval for the research was obtained from the Medical Ethics Review Board of the West China Hospital, Sichuan University. Informed consent was obtained from all study subjects. All studies were performed according to the Declaration of Helsinki.

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Peng, Y., Zhang, S., Zhao, Y. et al. Neutrophil extracellular traps may contribute to interstitial lung disease associated with anti-MDA5 autoantibody positive dermatomyositis. Clin Rheumatol 37, 107–115 (2018). https://doi.org/10.1007/s10067-017-3799-y

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