A, Clinical presentation. B, Microscopy showed acanthosis, cytoplasmic and nuclear vacuolation, increased dermal vascularity, and dense mixed infiltrate (hematoxylin-eosin stain; original magnification ×100). C, CD303/BDCA-2 immunostaining (counterstained with hematoxylin) highlights the presence of numerous plasmacytoid dendritic cells (+2 [the rating scale is described in the Table]) within the inflammatory infiltrate (original magnification ×100). D, Myxovirus protein A immunostaining (counterstained with hematoxylin) was diffuse and intense in the epithelium and inflammatory cells (original magnification ×100).
Saadeh D, Kurban M, Kibbi A, Abbas O. Involvement of Plasmacytoid Dendritic Cells in the Immunological Response Against Orf Infection. JAMA Dermatol. 2014;150(10):1112-1113. doi:10.1001/jamadermatol.2014.830
Plasmacytoid dendritic cells (PDCs) are specialized dendritic cells with a significant role in antiviral resistance.1,2 Plasmacytoid dendritic cells have never been studied in orf infection.
Our institutional review board approved the study. Archival materials with a diagnosis of orf infection and inflamed molluscum contagiosum (I-MC) were retrieved from our dermatopathology database. A total of 5 orf and 5 comparable I-MC cases fit the inclusion criteria. As described before,2 immunohistochemical analysis was performed on sections obtained from formalin-fixed, paraffin-embedded tissue using antibodies to BDCA-2 (mouse IgG1, clone 124B3.13, dilution 1:50; Dendritics) and myxovirus protein A (MxA) (M143, University of Freiburg, Germany; dilution 1:100).1,2 Although anti-BDCA-2 antibody is a specific PDC marker, anti-MxA antibody indirectly assesses PDC activity because MxA is an interferon (IFN)-α/β–inducible intracellular protein well established as a surrogate marker for local type I IFN production.1,2 We used a semiquantitative scoring system to assess PDC recruitment and MxA staining (Table).
Demographic data and results are summarized in the Table. Although PDCs were present in all orf (Figure) and I-MC cases, they were significantly less abundant in orf cases. Although the difference was not significant, orf cases tended to have less type I IFN production than I-MC cases.
Plasmacytoid dendritic cells exhibit plasma cell morphologic characteristics and express CD4, CD123, BDCA-2, and toll-like receptors 7 (TLR-7) and TLR-9 in endosomal compartments.1 They are capable of producing large quantities of type I IFNs against pathogenic agents.1 They not only provide antiviral resistance but also link innate and adaptive immunity by controlling function of myeloid dendritic cells, lymphocytes, and natural killer cells. In the skin, PDCs are involved in several infections (mainly viral), inflammatory processes (such as lupus and psoriasis), and malignant neoplasms.1,2 A parapox virus that infects sheep, orf can be transmitted to humans by direct inoculation and typically presents as a solitary lesion that progresses through several stages, including macular/popular, vesicular, nodular with weeping, papillomatous or verrucous, and finally dry crust. Healing occurs in 4 to 8 weeks.3,4 Characteristic histological features include parakeratotic crust, acanthosis, intraepidermal vesiculation, increased dermal vascularity, cytoplasmic and nuclear vacuolation, and dense mixed infiltrate composed of lymphocytes, histiocytes, neutrophils, and eosinophils.3,4 Despite its recently highlighted role against many cutaneous viral infections, such as I-MC and herpes,1,2 PDCs have never been studied in orf cases.
Albeit small, this study is the first to demonstrate the presence of PDCs in orf infection. This finding is probably mediated by the interaction of the parapox DNA virus with TLR-9, which usually recognizes DNA viruses. We confirmed previous findings that I-MC lesions are highly immunogenic with an ongoing PDC-mediated regression process.2 Similarly, PDCs were shown in our study to be part of the host response against orf infection, although significantly less abundant and tending to be less active (activity indirectly assessed by MxA expression because PDCs are the most potent producers of local type I IFN, secreting up to 1000 times more IFN-α/β than other cells) than in I-MC lesions.1,2 One explanation of this finding could be related to the early age of orf lesions studied (1-2 weeks in 4 cases), which is a limitation of our study, because PDC concentration and activity may differ at different stages of the infection. Early on, the orf virus releases immunomodulatory proteins, such as ovine IFN resistance protein and vascular endothelial growth factor E (inhibits development and functional dendritic cell maturation), that suppress the host’s immune reaction. This suppression allows the virus to replicate for some period before the host can mount an effective immune response.4 This finding is further supported by the reported effectiveness of imiquimod, an immunomodulator known to be a potent PDC activator through its effect on TLR-7, in clearing orf.5,6
Accepted for Publication: April 8, 2014.
Corresponding Author: Ossama Abbas, MD, Department of Dermatology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh/Beirut 1107 2020, Beirut, Lebanon (firstname.lastname@example.org).
Published Online: August 27, 2014. doi:10.1001/jamadermatol.2014.830.
Author Contributions: Dr Abbas had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Saadeh, Kurban, Abbas.
Critical revision of the manuscript for important intellectual content: Kibbi, Abbas.
Statistical analysis: Kurban, Abbas.
Administrative, technical, or material support: All authors.
Study supervision: Abbas.
Conflict of Interest Disclosures: None reported.
Additional Contributions: Myxovirus protein A was purchased from Otto Haller, MD, University of Freiburg, Germany.