Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage
Introduction
Plasmacytoid dendritic cells (PDC) has been extensively characterized in the last decades (Facchetti et al. 2003; Colonna et al. 2004; Liu 2005) and shown to correspond to a specialized cell population capable of producing large amounts on type I interferons (I-IFN) and differentiate into dendritic cells (Grouard et al. 1997; Cella et al., 1999, Cella et al., 2000). Animal models supporting a definitive role of PDC in pathology are still lacking, however, numerous studies have suggested their potential role in a variety of human diseases (Facchetti et al. 2003; Colonna et al. 2004). In particular, large amount of type I IFN produced by PDC seems to be relevant in the pathogenesis of lupus erythematosus [LE](Ronnblom and Alm 2001; Banchereau and Pascual 2006; Ronnblom and Pascual 2008), a complex disorder showing a broad spectrum of clinical manifestations, ranging from pure cutaneous form to a severe and progressive systemic disease [SLE]. The hallmark of LE pathogenesis is represented by loss of tolerance to variable nuclear antigen which leads to tissue deposition of immune complex followed by widespread inflammation and tissue damage. In this scenario, alterations in T and B lymphocyte function are retained the main culprit.
Recently, evidences pointed to a potential role of PDC in the pathogenesis of LE. PDC are the major producers of type I IFN, a key protein in the pathogenesis of this disease (Pascual et al. 2006; Gilliet et al. 2008). IFN therapy in cancer and viral infections induce autoantibodies formations in addition to other clinical features mimicking SLE (Ronnblom et al. 1991; Stewart 2003). Accordingly, patients with SLE display elevated level of type I IFN (Preble et al. 1982), which correlate with disease activity, and a type I IFN molecular signature in their peripheral blood cells (Blanco et al. 2001; Bennett et al. 2003; Baechler et al. 2004). This has been recently attributed to the presence of type I IFN inducers in the serum of LE patients (Bave et al., 2000, Bave et al., 2003; Lovgren et al. 2004; Barrat et al. 2005; Means et al. 2005). Notably, type I IFN production by PDC in vitro can be induced by SLE serum among a plethora of other stimuli (Dzionek et al. 2001). Surprisingly, PDC blood content is decreased in SLE patients (Cederblad et al. 1998); however, these cells have been found to infiltrate extra-lymphoid lesional tissues (Blomberg et al. 2001; Farkas et al. 2001) and locally produce type I IFN (Blomberg et al. 2001; Farkas et al. 2001; Wenzel et al. 2005). Skin homing of PDC can be driven in addition to other classical PDC-attracting chemokines (Penna et al. 2001; Vanbervliet et al. 2003), by anaphylotoxins C3a and C5a (Gutzmer et al. 2006), and by the recently identified chemotactic molecules Chemerin that binds its putative receptor ChemR23 expressed on lesional PDC(Vermi et al. 2005). Based on this large body of evidences, a major attention is now directed toward the understanding of the role of the tissue counterpart of PDC in the pathogenesis of the disease.
Recently published studies have documented the cutaneous accumulation of type I IFN producing PDC either in (Blomberg et al. 2001; Farkas et al. 2001; Wenzel et al. 2007a; McNiff and Kaplan 2008) a limited number of LE patients. Taking advantage on the availability of reagents recognizing PDC on fixed tissue, we studied a cohort of 74 patients and confirmed that cutaneous PDC infiltration represents the hallmark of LE. In particular, this population shows a dual compartmentalization in lesional skin. A dermal subset of PDC (D-PDC) is mainly found surrounding dermal vessels within nodules of inflammatory cells; D-PDC colocalize with DCLAMP+ myeloid DC and Th1-biased T-cells. A second subset of PDC is located at the dermo-epidermal junction (J-PDC) and colocalize with cytotoxic T-lymphocytes at the site apoptotic epithelial damage and immunocomplex deposition. We envisage that this topographical segregation of skin PDC provides direct proof to current models of LE pathogenesis (Pascual et al. 2006) and introduces a novel view of the role of these cells in autoimmunity.
Section snippets
Patients and tissues
The occurrence and distribution of PDC was studied on formalin-fixed paraffin embedded tissues from seventy-four skin biopsies and thirty renal biopsies from patients affected by LE (from the archive of the Department of Pathology, Spedali Civili di Brescia and Department of Dermatology, Medical University of Graz). Clinical data were provided for each case (Department of Dermatology, Rheumatology and Clinical Immunology, Spedali Civili of Brescia, Italy; Department of Dermatology, Medical
Cutaneous accumulation of PDC in lupus erythematosus
The occurrence of PDC was tested in 74 LE skin biopsies and seven normal control skin. PDC were identified based on their plasmacytoid morphology and expression of CD123, CD2ap (Marafioti et al. 2008) and BDCA-2 (Fig. 1). All these markers were suitable for the PDC identification on fixed tissues, although CD123+ cells were always slightly more numerous as revealed by double immunofluorescence staining (not shown). The large majority of LE biopsies (67/74; 90.5%)(Table 1) showed cutaneous
Discussion
In the last decade experimental evidences sustained the role of PDC in LE pathogenesis (Ronnblom and Alm 2001; Banchereau and Pascual 2006; Ronnblom and Pascual 2008) and it has been proposed that the interaction of type I IFN producing PDC with other leucocytes is central in the generation of auto-reactive clones and peripheral tissue damage [10]. PDC have been documented in lesional tissues of LE patients, (Blomberg et al. 2001; Farkas et al. 2001; Wenzel et al. 2007a; Fiore et al. 2008;
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