Role of the Chemokine Receptor CCR4 and its Ligand Thymus- and Activation-Regulated Chemokine/CCL17 for Lymphocyte Recruitment in Cutaneous Lupus Erythematosus

Abstract

Skin-infiltrating T lymphocytes are thought to play a major role in the pathogenesis of cutaneous lupus erythematosus (CLE). In this study, we investigated the role of the chemokine receptor 4 (CCR4) and its ligand thymus- and activation-regulated chemokine (TARC/CCL17) for the recruitment of T cells in inflamed skin of patients with CLE. We found significant numbers of CCR4+ T lymphocytes in the skin of all patients with CLE. Interestingly, a subset of patients with disseminated scarring skin involvement were characterized by both lesional and circulating CD8+ T cells expressing CCR4. Destruction of epidermal and adnexal structures was histomorphologically associated with CCR4+ cytotoxic T cells invading basal layers of the epidermis where keratinocytes showed apoptotic death. The CCR4 ligand TARC/CCL17 was strongly expressed in skin lesions and elevated in the serum of CLE patients. The functional relevance of lymphocytic CCR4 expression could be confirmed by TARC/CCL17-specific in vitro migration assays. Our investigations suggest that CCR4 and TARC/CCL17 play a role in the pathophysiology of CLE. In particular, cytotoxic CD8+ T cells expressing CCR4 appear to be involved in scarring subtypes of CLE.

Immunohistochemical characterization of the cellular infiltrate in discoid lupus erythematosus

“…It was detected that the number of CD8 + cells were appreciably higher than CD4 + cells in the DLE lesions. This was appreciably different from other authors (11,12), but a similar result was also obtained by Wenzel et al (13). The CD4/CD8 ratio, which ranged approximately from 0.7 to 1.7 (mean 1.0), was a slight decrease compared to that in normal skin (1.1), but there was no statistical significance between them.…”

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

“…The differences in the pathogenic mechanisms that lead to cutaneous lesions rather than severe organ involvement are not yet completely understood; however, skininfiltrating activated lymphocytes are thought to play a crucial role in the induction and maintenance of this autoimmune disease (5,6,33).…”

“…Peripheral blood was obtained from patients with various subtypes of CLE (SCLE, DLE, LET) (n ϭ 12) as well as from normal healthy donors (n ϭ 18) and separated by Ficoll gradient centrifugation. The detection of Treg by analysis of CD4ϩ,CD25 high cells has produced conflicting results in patients with SLE (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)31,32). Therefore, we used a new intracellular staining method to directly visualize Foxp3ϩ Treg by flow cytometry, which was performed according to the manufacturer's protocol, as described previously (25).…”

“…However, it remains unclear which processes limit CLE to the skin in most patients. Putative autoaggressive CD3ϩ T cell infiltrates can be detected in the cutaneous lesions, whereas no overt systemic autoimmune T cell dysfunction has been described (5,6). Accordingly, CLE might be attributable to a subtle local alteration in tolerance rather than a systemic failure of peripheral tolerance mechanisms as in SLE.…”

Cutaneous manifestations of systemic lupus erythematosus

“…Furthermore, it was shown that CXCR3 ligands, CXCL9, CXCL10, and CXCL11, are overexpressed in patients with CLE. Additionally, it has been reported that the CCR4 ligand TARC/CCL17 is increased in skin and in the serum of patients with CLE [30].…”