Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells

BACKGROUND: Lichen planus (LP) is a common inflammatory skin disease of unknown aetiology. Viral causes have been suggested. OBJECTIVES: To find candidate viruses associated with LP. METHODS: Lesional and nonlesional skin samples, peripheral blood mononuclear cells and serum were obtained from patients with LP. Ultrastructural, viral DNA, immunohistochemical and serological analyses were performed, and comparisons were made with psoriatic and normal skin. RESULTS: Electron microscopy revealed typical 120-200-nm enveloped particles with a 100-nm nucleus resembling human herpesvirus (HHV) virions both in dermis and in epidermis of lesional LP tissue. HHV-7 DNA was found in 11 of 18 lesional LP samples, as opposed to only one of 11 nonlesional LP samples (P =0.06), two of 11 lesional psoriasis samples (P = 0.05) and none of four normal skin samples. No relation was found between LP skin and DNA of other known HHVs (HHV-1-6 and 8). With immunohistochemistry, significantly more HHV-7+ cells were found in lesional LP epidermis than in normal epidermis. Lesional LP dermis contained significantly more HHV-7+ cells than nonlesional LP, psoriatic or normal dermis. Moreover, LP skin contained overwhelmingly and consistently more plasmacytoid dendritic cells (upregulated in virally induced conditions) than nonlesional LP samples. CONCLUSIONS: We conclude that HHV-7 replicates in LP lesions, but not in psoriasis, another inflammatory skin condition. HHV-7 is possibly involved in the pathogenesis of LP. These preliminary data make further research on this topic of interest.     

Lichen planus follicularis tumidus: Immunotyping of the inflammatory infiltrate with focus on plasmacytoid dendritic cells

Lichen planus follicularis tumidus (LPFT) is a rare clinicopathological variant of lichen planus (LP), clinically presenting with red-to-violaceous plaques studded with comedo-like lesions and keratin-filled milia-like cysts. Histopathologically, LPFT is characterized by cystically dilated follicular infundibula in the dermis, surrounded by a dense lichenoid lymphoid infiltrate with an associated interface reaction. We describe the clinicopathological features of an additional case of LPFT, focusing on the number and distribution of CD123(+) TCF4(+) plasmacytoid dendritic cells (pDCs). In our case, pDCs represented approximately 5% of the total inflammatory infiltrate, predominantly exhibiting a lichenoid distribution around the infundibula with no evidence of cluster formation, thus ruling out cutaneous lupus erythematosus. Our report is the first to describe the number and distribution of pDCs in LPFT. The results of our immunohistochemical analysis corroborate the notion that LPFT should be regarded as a rare variant of LP.     

单纯疱疹病毒2 gD基因的树突细胞疫苗免疫效应研究

【摘要】 目的 观察单纯疱疹病毒2 gD（HSV-2 gD）基因的树突细胞（DC）疫苗在动物实验中诱发特异性免疫应答情况。 方法 用腺病毒介导的、HSV-2 gD基因修饰的DC（pAdeno-HSV-2 gD-DC）疫苗免疫BALB/c小鼠3次,末次免疫后第10天检测小鼠血清中gD IgG水平;同时,分离小鼠脾淋巴细胞,用HSV-2gD蛋白刺激,MTT法检测小鼠脾淋巴细胞增殖情况、乳酸脱氢酶释放法测定细胞毒性T淋巴细胞（CTL）活性及ELISA法检测脾淋巴细胞培养上清中干扰素γ（IFN-γ）、白介素4（IL-4）水平。实验分为4组,pAdeno-DC组、pAdeno-HSV-2 gD-DC组、DC组、空白对照组,每组10只。 结果 pAdeno-HSV-2 gD-DC组小鼠血清内可检测到高滴度针对HSV-2gD蛋白的抗体（A450值为0.313 ± 0.034）,与pAdeno-DC组（0.034 ± 0.009）、DC组（0.028 ± 0.009）、空白对照组（0.026 ± 0.010）比较,差异有统计学意义（P < 0.05）。pAdeno-HSV-2 gD-DC可以诱导小鼠脾淋巴细胞增殖（刺激指数为1.600 ± 0.215）、有效杀伤靶细胞（CTL活性为37.1%）,与pAdeno-DC组（分别为1.063 ± 0.070和16.0%）、DC组（1.056 ± 0.063和14.9%）、空白对照组（1.020 ± 0.051和15.7%）比较,差异均有统计学意义（P < 0.05）。pAdeno-HSV-2 gD-DC组小鼠分离的脾细胞培养上清可以检测到高水平IFN-γ（A450值为0.568 ± 0.031）和IL-4（A450值为0.544 ± 0.043）,与pAdeno-DC组（0.266 ± 0.021和0.278 ± 0.037）、DC组（0.271 ± 0.023和0.275 ± 0.044）、空白对照组（0.252 ± 0.012和0.245 ± 0.051）比较,差异均有统计学意义（P < 0.05）。 结论 构建的pAdeno-HSV-2 gD-DC疫苗可以在小鼠中产生较强的特异性免疫应答。     

Tumor‐forming plasmacytoid dendritic cells associated with myeloid neoplasms. Report of a peculiar case with histopathologic features masquerading as lupus erythematosus

Plasmacytoid dendritic cells (PDC) belong to a subtype of dendritic cells that are normally absent in healthy skin. In some inflammatory diseases of the skin, especially lupus erythematosus (LE), these cells are occasionally recruited in great amounts, which can be used as a helpful clue for diagnosis. Rarely, PDC may also accumulate in the skin of patients with myeloid leukemia, a yet poorly known condition currently called ‘tumor‐forming PDC associated with myeloid neoplasms’. In this study, we describe a patient with unsuspected chronic myelomonocytic leukemia who developed cutaneous lesions characterized by a dermal infiltrate rich in PDC. Similarly to LE, such neoplastic PDC were accompanied by interface dermatitis‐like changes, but displayed an aberrant phenotype and shared the same chromosomal abnormality with the leukemic cells identified in the bone marrow, thus revealing the neoplastic nature of the process. This observation illustrates that tumor‐forming PDC associated with myeloid neoplasms may microscopically mimic LE in some patients. Accordingly, a hematologic workup is recommended in any skin lesion featuring excessive numbers of PDC, even if morphological alterations suggestive of interface dermatitis are found.     

Skin tumor formation in human papillomavirus 8 transgenic mice is associated with a deregulation of oncogenic miRNAs and their tumor suppressive targets

Background

Dysregulation of microRNA (miRNA) expression is regularly found in various types of cancer and contributes to tumorigenic processes. However, little is known about miRNA expression in non-melanoma skin cancer in which a pathogenic role of beta human papillomaviruses (HPV) is discussed. A carcinogenic potential of beta HPV8 could be demonstrated in a transgenic mouse model, expressing all early genes of HPV8 (HPV8-CER). A single UVA/B-dose induced oncogene expression and led to papilloma growth within three weeks.

Objective

Expression of miRNAs and their targets during HPV8-mediated tumor formation in mice.

Methods

Skin of untreated or UV-irradiated wild-type and HPV8-CER mice was analyzed for miRNA expression and localization by qPCR and in situ hybridization. MiRNA target protein expression was analyzed by immunohistochemical staining.

Results

Early steps in skin tumor formation in HPV8-CER mice were associated with an upregulation of the oncogenic miRNA-17-5p, -21 and -106a and a downregulation of the tumor-suppressive miRNA-155 and -206, which could be demonstrated by qPCR and in situ hybridization. The respective targets of miRNA-21 and -106a, the tumor suppressors PTEN, PDCD4 and Rb with their pivotal role in cell cycle regulation, apoptosis and proliferation were found to be downregulated.

Conclusion

This is the first report demonstrating that a cutaneous HPV type deregulates the expression of miRNAs. These deregulations are closely related to the UV-induced upregulation of HPV8 oncogene levels, which suggest a direct or indirect HPV8-specific effect on miRNA expression. These data presume that HPV8 interferes with the miRNA mediated gene regulation to induce tumorigenesis.