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Myeloid Dendritic Cells Are Major Producers of IFN-β in Dermatomyositis and May Contribute to Hydroxychloroquine Refractoriness

  • Author Footnotes
    4 These authors contributed equally to this work.
    Kristen L. Chen
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Search for articles by this author
  • Author Footnotes
    4 These authors contributed equally to this work.
    Jay Patel
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Search for articles by this author
  • Majid Zeidi
    Affiliations
    Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Maria Wysocka
    Affiliations
    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Muhammad M. Bashir
    Affiliations
    Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Basil Patel
    Affiliations
    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Spandana Maddukuri
    Affiliations
    Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Barbara White
    Affiliations
    Corbus Pharmaceuticals Holdings, Inc, Norwood, Massachusetts, USA
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  • Victoria P. Werth
    Correspondence
    Correspondence: Victoria P. Werth, Department of Dermatology, Perelman Center for Advanced Medicine, Suite 1-330A, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
    Affiliations
    Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Search for articles by this author
  • Author Footnotes
    4 These authors contributed equally to this work.
Published:March 03, 2021DOI:https://doi.org/10.1016/j.jid.2020.12.032
      Dermatomyositis pathogenesis remains incompletely understood; however, recent work suggests a predominant IFN-1 response. We explored dermatomyositis pathogenesis by quantifying the inflammatory cells in the skin, comparing myeloid with plasmacytoid dendritic cell release of IFN-β, and assessing myeloid dendritic cell (mDC) contribution to hydroxychloroquine refractoriness. Immunohistochemistry was performed to assess cell-type expression in lesional skin biopsies from 12 patients with moderate-to-severe cutaneous dermatomyositis. Immunofluorescence, laser-capture microdissection, and flow cytometry were used to assess mDC release of IFN-β in lesional skin biopsies and blood of patients with dermatomyositis. Immunohistochemistry was utilized to determine whether myeloid or plasmacytoid dendritic cells were increased in hydroxychloroquine nonresponders. CD4+, CD11c+, and CD69+ cells were more populous in lesional skin of patients with dermatomyositis. mDCs colocalized with IFN-β by immunofluorescence and laser-capture microdissection revealed increased IFN-β mRNA expression by mDCs in lesional skin of patients with dermatomyositis. In blood, both mDCs and plasmacytoid dendritic cells were major producers of IFN-β in patients with dermatomyositis, whereas plasmacytoid dendritic cells predominately released IFN-β in healthy controls (P < 0.01). mDCs were significantly increased in the skin of hydroxychloroquine nonresponders compared with that in the skin of responders (P < 0.05). mDCs cells appear to play an important role in dermatomyositis pathogenesis and IFN-β production.

      Abbreviations:

      FFPE (formalin fixed and paraffin embedded), HC (healthy control), HCQ (hydroxychloroquine), HPF (high-power field), KC (keratinocyte), LCM (laser-capture microdissection), mDC (myeloid dendritic cell), pDC (plasmacytoid dendritic cell)
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      References

        • Ali S.
        • Mann-Nüttel R.
        • Schulze A.
        • Richter L.
        • Alferink J.
        • Scheu S.
        Sources of type I interferons in infectious immunity: plasmacytoid dendritic cells not always in the driver's seat.
        Front Immunol. 2019; 10: 778
        • Anyanwu C.O.
        • Chansky P.B.
        • Feng R.
        • Carr K.
        • Okawa J.
        • Werth V.P.
        The systemic management of cutaneous dermatomyositis: results of a stepwise strategy.
        Int J Womens Dermatol. 2017; 3: 189-194
        • Beitnes A.C.
        • Ráki M.
        • Brottveit M.
        • Lundin K.E.
        • Jahnsen F.L.
        • Sollid L.M.
        Rapid accumulation of CD14+CD11c+ dendritic cells in gut mucosa of celiac disease after in vivo gluten challenge.
        PLoS One. 2012; 7: e33556
        • Bendewald M.J.
        • Wetter D.A.
        • Li X.
        • Davis M.D.
        Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota.
        Arch Dermatol. 2010; 146: 26-30
        • Bohan A.
        • Peter J.B.
        Polymyositis and dermatomyositis (first of two parts).
        N Engl J Med. 1975; 292: 344-347
        • Caproni M.
        • Torchia D.
        • Cardinali C.
        • Volpi W.
        • Del Bianco E.
        • D’Agata A.
        • et al.
        Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositis.
        Br J Dermatol. 2004; 151: 784-791
        • Chen M.
        • Quan C.
        • Diao L.
        • Xue F.
        • Xue K.
        • Wang B.
        • et al.
        Measurement of cytokines and chemokines and association with clinical severity of dermatomyositis and clinically amyopathic dermatomyositis.
        Br J Dermatol. 2018; 179: 1334-1341
        • Collin M.
        • Bigley V.
        Human dendritic cell subsets: an update.
        Immunology. 2018; 154: 3-20
        • Concha J.S.S.
        • Tarazi M.
        • Kushner C.J.
        • Gaffney R.G.
        • Werth V.P.
        The diagnosis and classification of amyopathic dermatomyositis: a historical review and assessment of existing criteria.
        Br J Dermatol. 2019; 180: 1001-1008
        • Crouse J.
        • Kalinke U.
        • Oxenius A.
        Regulation of antiviral T cell responses by type I interferons.
        Nat Rev Immunol. 2015; 15: 231-242
        • Crow M.K.
        • Ronnblom L.
        Type I interferons in host defence and inflammatory diseases.
        Lupus Sci Med. 2019; 6: e000336
        • Eguíluz-Gracia I.
        • Bosco A.
        • Dollner R.
        • Melum G.R.
        • Lexberg M.H.
        • Jones A.C.
        • et al.
        Rapid recruitment of CD14(+) monocytes in experimentally induced allergic rhinitis in human subjects.
        J Allergy Clin Immunol. 2016; 137: 1872-1881.e12
        • Fitzgerald-Bocarsly P.
        • Dai J.
        • Singh S.
        Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history.
        Cytokine Growth Factor Rev. 2008; 19: 3-19
        • Gallucci S.
        • Lolkema M.
        • Matzinger P.
        Natural adjuvants: endogenous activators of dendritic cells.
        Nat Med. 1999; 5: 1249-1255
        • Goreshi R.
        • Chock M.
        • Foering K.
        • Feng R.
        • Okawa J.
        • Rose M.
        • et al.
        Quality of life in dermatomyositis.
        J Am Acad Dermatol. 2011; 65: 1107-1116
        • Greenberg S.A.
        Dermatomyositis and type 1 interferons.
        Curr Rheumatol Rep. 2010; 12: 198-203
        • Grimm M.C.
        • Pullman W.E.
        • Bennett G.M.
        • Sullivan P.J.
        • Pavli P.
        • Doe W.F.
        Direct evidence of monocyte recruitment to inflammatory bowel disease mucosa.
        J Gastroenterol Hepatol. 1995; 10: 387-395
        • Hall J.C.
        • Rosen A.
        Type I interferons: crucial participants in disease amplification in autoimmunity.
        Nat Rev Rheumatol. 2010; 6: 40-49
        • Huard C.
        • Gullà S.V.
        • Bennett D.V.
        • Coyle A.J.
        • Vleugels R.A.
        • Greenberg S.A.
        Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis.
        Br J Dermatol. 2017; 176: 1224-1230
        • Jenner W.
        • Motwani M.
        • Veighey K.
        • Newson J.
        • Audzevich T.
        • Nicolaou A.
        • et al.
        Characterisation of leukocytes in a human skin blister model of acute inflammation and resolution.
        PLoS One. 2014; 9: e89375
        • Kao L.
        • Chung L.
        • Fiorentino D.F.
        Pathogenesis of dermatomyositis: role of cytokines and interferon.
        Curr Rheumatol Rep. 2011; 13: 225-232
        • Kiefer K.
        • Oropallo M.A.
        • Cancro M.P.
        • Marshak-Rothstein A.
        Role of type I interferons in the activation of autoreactive B cells.
        Immunol Cell Biol. 2012; 90: 498-504
        • Liao A.P.
        • Salajegheh M.
        • Morehouse C.
        • Nazareno R.
        • Jubin R.G.
        • Jallal B.
        • et al.
        Human plasmacytoid dendritic cell accumulation amplifies their type 1 interferon production.
        Clin Immunol. 2010; 136: 130-138
        • Magro C.M.
        • Segal J.P.
        • Crowson A.N.
        • Chadwick P.
        The phenotypic profile of dermatomyositis and lupus erythematosus: a comparative analysis.
        J Cutan Pathol. 2010; 37: 659-671
        • Mainetti C.
        • Terziroli Beretta-Piccoli B.
        • Selmi C.
        Cutaneous manifestations of dermatomyositis: a comprehensive review.
        Clin Rev Allergy Immunol. 2017; 53: 337-356
        • Sontheimer R.D.
        Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects.
        Dermatol Clin. 2002; 20: 387-408
        • Wong D.
        • Kea B.
        • Pesich R.
        • Higgs B.W.
        • Zhu W.
        • Brown P.
        • et al.
        Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases.
        PLoS One. 2012; 7: e29161
        • Zaba L.C.
        • Fuentes-Duculan J.
        • Eungdamrong N.J.
        • Abello M.V.
        • Novitskaya I.
        • Pierson K.C.
        • et al.
        Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells.
        J Invest Dermatol. 2009; 129: 79-88
        • Zeidi M.
        • Kim H.J.
        • Werth V.P.
        Increased myeloid dendritic cells and TNF-α expression predicts poor response to hydroxychloroquine in cutaneous lupus erythematosus.
        J Invest Dermatol. 2019; 139: 324-332