Spontaneous Regression of Highly Immunogenic Molluscum contagiosum Virus (MCV)- Induced Skin Lesions Is Associated with Plasmacytoid Dendritic Cells and.

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Spontaneous Regression of Highly Immunogenic Molluscum contagiosum Virus (MCV)- Induced Skin Lesions Is Associated with Plasmacytoid Dendritic Cells and IFN-DC Infiltration William Vermi, Simona Fisogni, Laura Salogni, Leo Schärer, Heinz Kutzner, Silvano Sozzani, Silvia Lonardi, Cristina Rossini, Piergiacomo Calzavara-Pinton, Philip E. LeBoit, Fabio Facchetti Journal of Investigative Dermatology Volume 131, Issue 2, Pages 426-434 (January 2011) DOI: 10.1038/jid.2010.256 Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Cytotoxic T-cell infiltration and apoptotic cell death characterize inflammatory Molluscum contagiosum (I-MC). Sections from non-inflamed Molluscum contagiosum (NI-MC; a) and I-MC (b–h) are immunostained for CD45RB (a, b), CD3 (c), CD8 (d1 and d2), CD30 (e), perforin (d1), granzyme B (GrB; d2 and e), T-bet (f1), Foxp3 (f2), hematoxylin/eosin (g), and cleaved caspase 3 (h). In NI-MC, scattered CD45+ cells are observed (a), whereas I-MC are densely infiltrated by CD45+ leukocytes (b); intraepithelial inflammatory cells are very rare. I-MC contain numerous CD3+ T cells (c), including CD8+perforin+ (d1), CD8+GrB+(d2), and CD30+ GrB+ cells (e, inset). The large majority of T cells express T-bet (f1), with only rare Foxp3+ cells (f2). In I-MC, numerous apoptotic keratinocytes occur at the boundary between epithelium and stroma (g, inset, h). Secondary antibodies are revealed with diaminobenzidine (DAB; brown in a–f and h), new fucsin (red, CD8 in d2), and Ferangi blue (blue, CD8 in d1 and CD30 in e). Original magnification × 40 (a–c; scale bar=500μm), × 200 (e, g, and h; scale bar=100μm), and × 400 (d1, d2, f1, f2, and insets in e and g; scale bar=50μm). Journal of Investigative Dermatology 2011 131, 426-434DOI: (10.1038/jid.2010.256) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Differential expression of major histocompatibility complex (MHC)-I, MHC-II, TAP1, and NF-κB in Molluscum contagiosum (MC). Sections from non-inflamed MC (NI-MC; a, c, e, and g) and inflammatory MC (I-MC; b, d, f, and h) are immunostained for major histocompatibility complex-11 (MHC-II; a, b), MHC-I (c, d), TAP1 (e, f), and NF-κB (g, h). In NI-MC, MHC-II (a), MHC-I (c), and TAP1 (e) are restricted to stromal cells and, for MHC-I and TAP1, to areas of normal skin. I-MC shows strong reactivity for all these molecules (b, d, and f with corresponding insets), at the periphery of infected epithelium. In NI-MC, NF-κB is restricted to the cytoplasm (g), whereas the same molecule localizes to the nucleus of keratinocytes in I-MC (h). Secondary antibodies revealed with diaminobenzidine (DAB). Original magnification × 40 (a–f; scale bar=500μm), × 200 (g and h; scale bar=100μm), and × 400 (insets in b, d, and f; scale bar=50μm). Journal of Investigative Dermatology 2011 131, 426-434DOI: (10.1038/jid.2010.256) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Accumulation of plasmacytoid dendritic cells (PDCs) in inflammatory Molluscum contagiosum (I-MC) is associated with type I IFN protein expression signature. Sections from I-MC (a–e, g) and non-inflamed (NI)-MC (f and h) are immunostained for CD123 (a), BDCA2 (b–d), granzyme B (GrB; c and d), MxA (e and f), and STAT1pY701 (g and h). In I-MC, PDCs occur in the deep dermis or surround islands of infected epithelium (a, b) and may contain large GrB+ granules (c), or totally lack GrB reactivity (d, black arrows). In I-MC, a diffuse and strong reactivity for MxA (e) and nuclear STAT1pY701 (g) of keratinocytes and inflammatory cells is obvious (inset in g). In NI-MC, reactivity for MxA and STAT1pY701 is weak and focal (f and h). Secondary antibodies revealed with diaminobenzidine (DAB; brown in a–h) and Ferangi blue (blue, BDCA2 in c and d). Original magnification × 40 (a, e–h; scale bar=500μm), × 100 (a; scale bar=200μm), × 200 (b; scale bar=100μm), × 400 (inset in g; scale bar=50μm), and × 600 (c and d; scale bar=20μm). Journal of Investigative Dermatology 2011 131, 426-434DOI: (10.1038/jid.2010.256) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Expression of IFNs and IFN-inducible genes in Molluscum contagiosum (MC). Gene expression was evaluated using mRNA extracted from inflammatory MC (I-MC) and non-inflamed MC (NI-MC). mRNA expression (2-ΔCT) was normalized to 18S rRNA. Results are expressed as arbitrary units. Journal of Investigative Dermatology 2011 131, 426-434DOI: (10.1038/jid.2010.256) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 IFN-induced dendritic cells (IFN-DCs) occur in inflammatory Molluscum contagiosum (I-MC) lesions. All sections are from I-MC and stained for CD123 (a), CD11c (b, d, f, and h2), hematoxylin/eosin (c), active caspase-3 (d), CD14 (e1), CD16 (e2), TRAIL (f1), GrB (f2), CCR7 (g1), CD83 (g2), CD40 (g3), MHC-II (g4), MxA (h1), and STAT1pY701 (h2). Serial sections (a, b) illustrate numerous large CD123+ cells (a) coexpressing CD11c (b) with round-to-elongated nucleus and ample cytoplasm (c), localized in areas of keratinocytes apoptosis (a–d and f). These cells express CD14 (e1), CD16 (e2), CCR7 (g1), CD40 (g3), MHC-II (g4), MxA (h1), and STAT1pY701 (h2). A more limited fraction is also positive for TRAIL (f1) GrB (f2) and CD83 (g2). Secondary antibodies revealed with diaminobenzidine (DAB; brown in a, b, d–h2), new fucsin (red, CD11c in f2 and h2), and Ferangi blue (blue, CD11c in d and f1). Original magnification × 200 (a, b, and f; scale bar=100μm), × 400 (c–e, g, h; scale bar=50μm). Journal of Investigative Dermatology 2011 131, 426-434DOI: (10.1038/jid.2010.256) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Characterization of monocyte-derived IFN-induced dendritic cells (IFN-DCs). IFN-DCs expressed variable levels of CD14 and CD1a. CD1a expression inversely correlated with the expression of MxA, CD16, and CD14 (a). IFN-DCs strongly express CD123+ and CD11c+ (b) and during their differentiation upregulate FasL and TRAIL that are at higher levels than those observed in classic monocyte-derived DCs obtained in the presence of GM-CSF and IL-4 (b). Journal of Investigative Dermatology 2011 131, 426-434DOI: (10.1038/jid.2010.256) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions