Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions

Abstract

Plasmacytoid dendritic cell (P-DC) precursors in peripheral blood produce large amounts of interferon (IFN)-alpha/beta when triggered by viruses. However, when incubated with interleukin-3 and CD40 ligand, the same precursors differentiate into mature DCs that stimulate naïve CD4(+) T cells to produce Th2 cytokines. We recently reported that P-DCs accumulate in nasal mucosa of experimentally induced allergic rhinitis, supporting a role for this DC subset in Th2-dominated inflammation. Here we examined whether P-DCs accumulate in cutaneous lesions of lupus erythematosus (LE), a disorder associated with increased IFN-alpha/beta production. Our results showed that P-DCs were present in 14 out of 15 tissue specimens of cutaneous LE lesions, but not in normal skin. Importantly, the density of P-DCs in affected skin correlated well (r(s) = 0.79,P < 0.0005) with the high number of cells expressing the IFN-alpha/beta-inducible protein MxA, suggesting that P-DCs produce IFN-alpha/beta locally. Accumulation of P-DCs coincided also with the expression of L-selectin ligand peripheral lymph node addressin on dermal vascular endothelium, adding further support to the notion that these adhesion molecules are important in P-DC extravasation to peripheral tissue sites. Together, our findings suggested that P-DCs are an important source of IFN-alpha/beta in cutaneous LE lesions and may therefore be of pathogenic importance.

Figure 1.

In situ phenotypic characterization of CD123^high P-DCs and related MxA and PNAd expression. Multicolor immunofluorescence staining for: CD123 (Cy3, red), CD45RA (FITC, green), and cytokeratin (AMCA, blue in c) (a, c, and d); human MxA (Cy3, red) with nuclear counterstain (DAPI, blue) (b); CD123 (Cy3, red) (e–g) and HLA-DR (FITC, green) (e), CD68 (FITC, green) (f), human c-kit (Alexa Fluor 488, green) (g); CD3 (Cy3, red) and CD45RA (FITC, green) (h); and PNAd revealed with mAb MECA-79 (Cy3, red) and endothelium with Ulex europaeus lectin-1 (FITC, green) (i) in serial sections (comparable fields in a and b) of cutaneous DLE lesion. Characteristic accumulation of CD123^highCD45RA⁺ cells (yellow staining) along the dermal-epidermal junction (a), around hair follicles (c), and adjacent to dermal vessel (asterisk) with endothelial CD123 expression (d); note strong expression of MxA in keratinocytes and infiltrating cells in dermis (b) in field comparable to high numbers of P-DCs (a). CD123^high cells also express HLA-DR (e) and CD68 (f); the intracellular dot-like staining pattern for CD68 was similar in tonsillar tissue (not shown) and found characteristic for DCs by others. Dermal c-kit⁺ mast cells do not express CD123 (g, arrowhead); note the large number of naïve (CD3⁺CD45RA⁺) T cells (yellow staining, some arrowed) (h). Medium–sized vessels (diameter, ≥10 μm) with strong PNAd expression appears yellow (i); note that some keratinocytes also react with MECA as previously noted. Basement membrane of epidermis is indicated by dashed line. Original magnifications: ×200 (a and b); ×400 (c, d, g, and h); ×630 (e and f); ×100 (i).

Figure 2.

Relationship between the density (cell/mm²) of P-DCs (CD123^highCD45RA⁺ cells) and MxA⁺ cells in cutaneous LE lesions (r_s= 0.79, P < 0.0005, n = 15). Based on data in Table 1 ▶ and Spearman’s rank correlation test.