Possible role of plasmacytoid dendritic cells in pityriasis lichenoides.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) and their product, type I interferons (IFNs), have been implicated in the pathogenesis of several skin disorders characterized by an interface dermatitis (ID) pattern, such as lichen planus (LP). A type I IFN signature has previously been documented in pityriasis lichenoides (PL). Although pDCs are known to be the main source and most potent producers of local type I IFNs, their role in PL has not been investigated. AIM: To investigate the role of pDCs in PL. METHODS: In total, 20 cases of PL and 20 comparable cases of LP were immunohistochemically tested for pDC occurrence and type I IFN production using anti-blood-derived dendritic cell antigen-2 (BDCA2; a specific pDC marker) and anti-myxovirus protein A (anti-MxA) antibodies (indirect marker of pDC activity), respectively. MxA is a well-established surrogate marker for local type 1 IFN production. A semiquantitative scoring system was used. RESULTS: pDCs were present in all 40 cases with no statistically significant difference between the two groups. MxA expression was intense and diffuse in the majority of PL and LP cases. CONCLUSIONS: pDCs constitute a central component of the inflammatory infiltrate in PL, suggesting that PL shares with the other entities that exhibit an ID a common pDC-driven process through type I IFN production, which ultimately leads to the cytotoxic attack.

Plasmacytoid dendritic cells and type I interferon in the immunological response against warts.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) are the most potent producers of type I interferons (IFNs), and are involved in the pathogenesis of several cutaneous infectious (especially viral), inflammatory/autoimmune and neoplastic entities. Their role in the pathogenesis and regression of human papilloma virus (HPV)-induced skin lesions has not been well studied. AIM: To investigate pDC occurrence and activity in HPV-induced skin lesions, including inflamed and uninflamed warts as well as epidermodysplasia verruciformis (EDV)-associated lesions. METHODS: In total 20 inflamed and 20 uninflamed HPV-induced skin lesions (including 7 EDV lesions) were retrieved from our database, and the tissue was immunohistochemically tested for pDC occurrence and activity using anti-BDCA-2 and anti-MxA antibodies, respectively. RESULTS: pDCs were present in all 20 inflamed warts and absent from all 20 uninflamed cases. MxA expression was also diffuse and strong in 75% (15/20) inflamed warts, but not in any of the uninflamed warts. CONCLUSIONS: pDCs constitute a central component of the inflammatory host response in inflamed warts, possibly contributing to their regression through production of type I interferons.

A novel mutation in the RSPO4 gene in a patient with autosomal recessive anonychia.

The Wnt signalling pathway is a major pathway involved in the embryogenic development of the various organs of the body. Appropriate signalling in this pathway relies on the proper functioning of several proteins including the R-spondin family of proteins. Deactivating mutations in R-spondin 4 are associated with anonychia. We present the case of a 26-year-old man presenting with anonychia of the 20 nails, which had been present since birth. Using genetic studies, we identified a novel nonsense mutation, c.164-165TC>AA, characterized by two consecutive mismatch bases. To our knowledge, this mutation is the first to be reported in R-spondin 4 in a Lebanese population. Evaluating new patients with anonychia provides fruitful clinical and molecular findings.

Erythropoietic protoporphyria a clinical and molecular study from Lebanon: Ferrochelatase a potential tumor suppressor gene in colon cancer.

Erythropoietic protoporphyria (EPP) is a rare cutaneous and systemic disease caused by mutations in the ferrochelatase gene (FECH). The molecular underpinnings of EPP in Middle Eastern populations and relative to other ethnic groups secondary to increased consanguinity are unknown. To understand the molecular pathogenesis of Middle Eastern EPP, we surveyed clinicopathological and molecular features in 6 large consanguineous families from Lebanon and Syria presenting with cutaneous and systemic features consistent with EPP. We observed 30% increased liver disease and 20% elevated end-stage liver complications in our EPP cohort compared to EPP patients previously reported elsewhere. In addition, Middle Eastern EPP patients in our cohort exhibited uniquely an increased incidence of colon cancer. Sequence analysis revealed 2 novel non-synonymous FECH mutations in the studied families designated p.M294T and p.I230M. In addition, FECH activity was significantly decreased (6%) in fibroblasts obtained from sun-exposed sites in a patient with p.M294T mutation, whereas in sharp contrast, protected sites from the same patient exhibited 54% activity for the gene. We also found that sun-exposed fibroblasts, relative to sun-protected and control fibroblasts, exhibited suppressed growth and atypical morphology in vitro, and that these effects were alleviated when the cells were co-cultured with sun-protected fibroblasts. Our findings on the increased incidence of colon cancer in EPP patients prompted us to survey FECH expression patterns in cancer. Using publicly available microarray datasets we found that FECH mRNA was largely significantly decreased in colon adenocarcinomas relative to normal colon tissues. Our findings suggest that families with autosomal recessive EPP should be screened more extensively for systemic involvement including liver diseases and colon cancer, and point to a previously unknown yet plausible tumor suppressor role for FECH in colon malignancy.

Genetics of syndromic and non-syndromic hereditary nail disorders.

The nail is a unique epithelial skin appendage made up of a fully keratinized nail plate. The nail can be affected in several systemic illnesses, dermatological diseases, and inherited nail disorders. Nail dystrophies can present as isolated disorders or as a part of syndromes. Substantial progress has been achieved in the management and diagnosis of nail diseases; however, not much is known about the underlying molecular controls of nail growth. The homeostasis and development of the nail appendage depend on the intricate interactions between the epidermis and underlying mesenchyme, and comprise different signaling pathways such as the WNT signaling pathway. Digit-tip regeneration in mice and humans has been a known fact for the past six decades; however, only recently the underlying biological mechanisms by which the nail organ achieves digit regeneration have been elucidated. Moreover, significant progress has been made in identifying nail stem cells and localizing stem cell niches in the nail unit. More fascinating, however, is the role they play in orchestrating the processes that lead to the regeneration of the digit. Further elucidating the role of nail stem cells and the signaling pathways driving epithelial-mesenchymal interactions in the nail unit might contribute to the development of novel therapeutic tools for amputees.

Plasmacytoid dendritic cells in alopecia areata: missing link?

BACKGROUND: Type I interferon (IFN) signature has been implicated in alopecia areata (AA). However, type I IFN source has never been documented. Plasmacytoid dendritic cells (PDCs) are generally known to be the main source and most potent producers of local type I IFNs. Their role in AA pathogenesis has never been investigated. OBJECTIVE: Investigate PDC role in AA. METHODS: Nineteen AA cases were retrieved from our database and were immunohistochemically tested for PDC occurrence and activity using anti-BDCA-2 and anti-MxA antibodies respectively. Comparison to 10 trichotillomania and 7 androgenetic alopecia (AGA) cases was also done. RESULTS: Plasmacytoid dendritic cells were present in all AA cases in a peri-bulbar location and, as indirectly assessed by MxA expression, were in an active state producing type I IFNs. All trichotillomania cases showed the presence of PDCs, though significantly less abundant and in a different distribution (mainly superficial perivascular) than that in AA. PDC presence and MxA expression were absent in AGA. CONCLUSIONS: Plasmacytoid dendritic cells constitute a central component of the peribulbar infiltrate in AA suggesting a significant role in AA pathogenesis. Additionally, PDC distribution could help in microscopically differentiating AA from trichotillomania or AGA.

Metformin in dermatology: an overview.

For several decades, metformin has been used as an oral hypoglycaemic agent, where it is the first line of treatment in overweight and obese type 2 diabetic patients. This is because it decreases the hepatic glucose output and acts as an insulin sensitizer by increasing the glucose utilization by muscles and adipocytes. As a result of the improvement in glycaemic control, serum insulin concentrations decline slightly, thus improving hyperinsulinaemia and its signs. In addition, it has been shown that metformin has platelet anti-aggregating and antioxidant effects. These pharmacological properties have allowed metformin to be effective in non-diabetic situations including cutaneous conditions. This is an evidence-based review on the use of metformin in the treatment of skin disorders such as hirsutism, acne, hidradenitis suppurativa, acanthosis nigricans, psoriasis, skin cancer, among others. In addition, cutaneous side-effects such as leukocytoclastic vasculitis, bullous pemphigoid, psoriasiform drug eruption, lichen planus and acute alopecia have been associated with metformin use and are discussed in the article.

Clinicopathological study of 81 cases of localized and systemic scleroderma.

BACKGROUND: Scleroderma is a connective tissue disease that includes localized and systemic forms. Our recent encounter with a morphea case exhibiting prominent perineural inflammation microscopically prompted us to assess the features of all patients diagnosed with morphea/scleroderma at our institution. OBJECTIVE/METHODS: To describe the clinicopathological features of all patients diagnosed with morphea/scleroderma at American University of Beirut Medical Center (AUB-MC) between 1999 and 2010, and compare our findings with those published in the literature. RESULTS: A total of 81 cases (63 women and 18 men) were identified, of which 73 were localized (morphea) and eight were systemic scleroderma. Clinically, plaque type morphea was the most common variant both in adults and children, and seven (9%) cases of morphea were associated with lichen sclerosis et atrophicus (LSA). Histopathologically, perineural inflammation was observed in 49% of cases, and may serve, in addition to other features including lichen sclerosis-like changes (observed in exclusively nine cases of morphea), more diffuse dermal and less subcutaneous sclerosis, and intense inflammation, as clues favouring diagnosis of morphea over systemic sclerosis. CONCLUSION: The features of morphea/scleroderma patients in this study are generally comparable to those published in the literature, with few differences. Clinically, plaque type morphea was the most common variant both in adults and children and LSA was a frequent association. Histopathologically, perineural inflammation was commonly observed and may serve in addition to lichen sclerosis-like changes and intense inflammation as clues favouring diagnosis of morphea over systemic sclerosis.

Mutations in LPAR6/P2RY5 and LIPH are associated with woolly hair and/or hypotrichosis.

BACKGROUND: Woolly hair (WH) belongs to a family of disorders characterized by hair shaft anomalies that clinically presents with tightly curled hair, which can be divided into syndromic and non-syndromic forms of WH. We have recently identified mutations in both LPAR6/P2RY5 and LIPH that are associated with autosomal recessive woolly hair (ARWH). OBJECTIVE: To study the underlying genetic causes of autosomal woolly hair in Pakistani population. METHODS: We studied 10 Pakistani families with ARWH for mutations in LPAR6/P2RY5 and LIPH and then performed haplotype analysis to confirm their segregation in the families. RESULTS: We identified five mutations in LPAR6/P2RY5, among which three were recurrent and two were novel in eight Pakistani families. We then showed that two of the mutations in LPAR6/P2RY5 are founder mutations in Pakistani families. Moreover, we identified two recurrent mutations in the LIPH gene in two Pakistani families. CONCLUSION: Our study extends the spectrum of mutations in LPAR6/P2RY5 gene and underscores those mutations in LPAR6/P2RY5 and LIPH result in similar phenotypes.