title: The host defense peptide LL-37 a possible inducer of the type I interferon system in patients with polymyositis and dermatomyositis.
abstract: The type I interferon (IFN) system has recently been suggested to play important and essential roles in the pathogenesis of myositis. However, a clarification of how type I IFNs could function as triggering factor(s) in the pathogenesis of myositis has yet failed. Through activation of the type I IFN system, the host defense peptide LL-37 carries numerous immunomodulatory properties and is implicated in the pathogenesis of several other autoimmune diseases, including systemic lupus erythematosus (SLE). The expression of LL-37 can be regulated by various endogenous factors including the active form of vitamin D (25(OH)D3). The aim of this study was to explore a potential role of LL-37 in relation to the type I IFN system in patients with polymyositis (PM) and dermatomyositis (DM) and to compare these with SLE patients and healthy controls. We investigated muscle (3 PM, 5 DM) and symptomatic (5 DM) and non-symptomatic (3 PM, 3 DM) skin biopsies from patients with short disease duration and muscle biopsies (3 PM, 1 DM) from patients with long disease duration. Six SLE patients with symptomatic and non-symptomatic skin and five muscle and six skin biopsies from healthy individuals served as controls. Tissue specimens were immunohistochemically stained for LL-37, neutrophils (CD66b), plasmacytoid dendritic cells (BDCA-2), myxovirus resistance protein A (MxA), and macrophages (CD68, CD163). In addition, LL-37 and CD66b double staining was also performed. Serum levels of 25(OH)D3were investigated in PM and DM patients with short disease duration (3 PM, 5 DM) and in 40 healthy controls. We found that the expression of LL-37, BDCA-2 (the major producer of type I IFNs), MxA (an interferon-inducible protein), and macrophages were higher in muscle tissue of PM and DM patients compared to healthy controls. The LL-37 expression was mainly derived from neutrophils. Neutrophils were increased in both symptomatic and non-symptomatic skin of myositis and SLE patients and BDCA-2 was increased in symptomatic DM skin when compared to healthy controls. Moreover, the expression of MxA in symptomatic and non-symptomatic skin of SLE patients was higher when compared to both myositis patients and healthy controls. There was no difference in the expression of LL-37 in skin of myositis and SLE patients compared to healthy controls. All PM and DM patients with a short disease duration had low 25(OH)D3levels compared to healthy controls. In conclusion, the present study supports our hypothesis that LL-37 may activate type I IFNs, which could initiate and perpetuate an inflammatory process. The prolonged exposure of the immune system to type I IFNs may eventually break tolerance and lead to autoimmune myositis.
authors.affiliation: Department of Rheumatology, China-Japan Friendship Hospital, Beijing, China; Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Quan
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Monica
authors.initials: M
authors.lastname: Lindh
authors.affiliation: Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Maryam
authors.initials: M
authors.lastname: Dastmalchi
authors.affiliation: Department of NVS, Division of Physiotherapy, Karolinska Institutet, Huddinge, Stockholm, Sweden; Functional Area Occupational Therapy and Physical Therapy, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Alexanderson
authors.affiliation: Department of Clinical Sciences, Division of Dermatology, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Popovic Silwerfeldt
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.affiliation: Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.affiliation: Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. Electronic address: Cecilia.Wick@ki.se.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wick
mesh_terms: D000328:Adult; D000368:Aged; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology; D015415:Biomarkers; D001706:Biopsy; D016022:Case-Control Studies; D003882:Dermatomyositis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D017285:Polymyositis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D001323:Autoantibodies; D015415:Biomarkers; D007370:Interferon Type I; D054804:Cathelicidins
keywords: Innate immunity; Interferon; LL-37; Myositis; Systemic lupus erythematosus