Enhanced Type I Interferon Signalling Promotes Th1-biased Inflammation in Cutaneous Lupus Erythematosus

J Pathol. 2005 Mar;205(4):435-42. doi: 10.1002/path.1721.

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.

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Chemokine CXCL10
  • Chemokines, CXC / analysis
  • Female
  • GTP-Binding Proteins / analysis
  • Humans
  • Immunity, Cellular / immunology
  • Interferon Type I / immunology*
  • Keratinocytes / immunology
  • Lupus Erythematosus, Cutaneous / immunology*
  • Lupus Erythematosus, Discoid / immunology
  • Male
  • Myxovirus Resistance Proteins
  • Receptors, CXCR3
  • Receptors, Chemokine / immunology
  • Signal Transduction / immunology*
  • Skin / immunology
  • Th1 Cells / immunology*

Substances

  • CXCL10 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL10
  • Chemokines, CXC
  • Interferon Type I
  • MX1 protein, human
  • Myxovirus Resistance Proteins
  • Receptors, CXCR3
  • Receptors, Chemokine
  • GTP-Binding Proteins