title: Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.
abstract: Recent studies have suggested that type I interferons (IFN) play a role in the pathogenesis of lupus erythematosus (LE), an autoimmune disease of unknown aetiology. Natural interferon-producing plasmacytoid cells have been demonstrated in cutaneous LE (CLE) lesions, along with elevated levels of IFN-alpha mRNA. The hypothesis in the current study was that local production of type I IFNs in CLE induces Th1-biased inflammation via induction of IFN-inducible chemokines such as IP10/CXCL10 leading to the recruitment of chemokine receptor CXCR3 expressing T-cells into skin lesions. Skin biopsies from 21 patients suffering from different types of active cutaneous LE were analysed for the expression of MxA, a protein specifically induced by type I interferons, the IFN-inducible protein IP10/CXCL10, and the chemokine receptor CXCR3, characteristic for Th1 cells, by immunohistochemistry. Additionally, peripheral CD4+ and CD8+ T-cells were investigated for the expression of MxA and CXCR3 by flow cytometry. Cutaneous LE lesions were characterized by strong expression of MxA indicating the induction of localized type I IFN signalling in the skin. Large numbers of infiltrating CXCR3 positive lymphocytes were detected in CLE skin lesions, and correlated closely with lesional MxA expression (epidermis: Spearman's rho = 0.56, p < 0.001; dermis: rho = 0.82, p < 0.001). Intracellular MxA levels of circulating CD4+ and CD8+ T-cells were significantly enhanced in patients with active CLE lesions. The percentage of peripheral T-cells expressing CXCR3 was significantly decreased in specific CLE subtypes. Expression of IP10/CXCL10 in the epidermis links type I IFN signalling and recruitment of CXCR3+ T cells. These results suggest an important role for type I interferon signalling in the pathogenesis of cutaneous lupus erythematosus. It is proposed that type I IFNs induce a Th1-biased inflammatory immune response, with recruitment of CXCR3-expressing T-lymphocytes into the skin.
authors.affiliation: Department of Dermatology, University of Bonn, Germany. joerg.wenzel@ukb.uni-bonn.de
authors.forename: Joerg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Eva
authors.initials: E
authors.lastname: Wörenkämper
authors.forename: Silke
authors.initials: S
authors.lastname: Freutel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Henze
authors.forename: Otto
authors.initials: O
authors.lastname: Haller
authors.forename: Thomas
authors.initials: T
authors.lastname: Bieber
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000032:analysis; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology; D008178:Lupus Erythematosus, Cutaneous / Q000276:immunology*; D008179:Lupus Erythematosus, Discoid / Q000276:immunology; D008297:Male; D064547:Myxovirus Resistance Proteins; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D012867:Skin / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D007370:Interferon Type I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D019204:GTP-Binding Proteins