Vascular endothelial growth factor (VEGF-a) in Fabry disease: association with cutaneous and systemic manifestations with vascular involvement.

INTRODUCTION: Fabry disease is an X-linked inherited metabolic disorder characterized by the deficiency of lysosomal α-galactosidase A enzyme. This leads to the accumulation, into lysosomes through the body, of glycosphingolipids, mainly Gb3. Skin involvement and progressive multi-organ failure are usually observed. Endothelium is the preferential target of the Gb3 storage that determines endothelial dysfunction and vasculopathy leading to the clinical manifestations of the disease. The serum levels of Vascular Endothelial Growth Factor-A (VEGF-A), a specific endothelial cell mitogen, were analyzed in Fabry patients to explore a possible association to the clinical manifestations with vascular involvement. METHODS: Thirty-five patients with a biochemical and genetic diagnosis of Fabry disease, along with an age-gender-matched healthy control group, were enrolled. Serum samples were collected and analyzed by ELISA. The genetic mutations, the specific organ dysfunction, and the cardiovascular risk factors such as dyslipidaemia, diabetes, smoking habits and hypertension were evaluated in Fabry patients. RESULTS: The mean serum level of VEGF-A in Fabry patients group was significantly higher than in the control group (P=0.006). A statistical significant association, between VEGF-A levels and the skin manifestation including angiokeratomas, sweating abnormalities and Fabry Facies was found. An association was also found between high VEGF-A and specific GLA mutations, the male gender, the renal and neurological manifestations, the presence of eye vessels tortuosity, smoking habit and hypertension. CONCLUSIONS: We detected increased VEGF-A levels in patients with Fabry disease compared to the controls, and we hypothesized that this could be a response to the vascular damage characterising this lysosomal disorder. However, further studies are necessary to clarify the role of VEGF-A in Fabry.

Acquired epidermodysplasia verruciformis: a comprehensive review and a proposal for treatment.

BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by immunologic abnormalities, disseminated human papilloma virus infection, and early development of skin cancers. Acquired forms have been rarely reported and usually occur with immunosuppression. The therapeutic management of the acquired forms is not standardized, and several therapies have been tried, with variable outcomes. OBJECTIVES: To provide updated clinical and experimental information on the treatment of acquired EV. METHODS: A Medline literature search was performed for relevant Medical Subject Heading terms, reviewing publications on strategies for management of acquired EV. We also report a case successfully treated using a combination of photodynamic therapy and oral retinoids. CONCLUSION: Data from the literature show that a standardized approach to this condition is lacking; the combination treatment chosen in our case may be proposed because it led to an excellent clinical outcome and a long-lasting remission.

A possible role for CD8+ T lymphocytes in the cell-mediated pathogenesis of pemphigus vulgaris.

Pemphigus vulgaris (PV) is an autoimmune blistering disease whose pathogenesis involves both humoral and cell-mediated immune response. Though the pathogenetic role of autoantibodies directed against desmoglein 3 is certain, a number of other factors have been suggested to determine acantholysis in PV. In this study we examined the possible role of CD8+ T cells in the development of acantholysis by a passive transfer of PV autoantibodies using CD8 deficient mice, and we also studied the inflammatory infiltrate of PV skin lesions by immunohistochemical staining. The results of the immunohistochemical staining to study the expression of CD3, CD4, and CD8 in PV skin lesions showed that CD4+ are more expressed than CD8+ in the inflammatory infiltrate of PV lesions, confirming the data of the previous literature. The passive transfer study showed a lower incidence of pemphigus in the group of CD8 deficient mice compared to the control one of wild-type mice. These results suggest that CD8+ T cells may play a role in the pathogenesis of PV, perhaps through the Fas/FasL pathway.

Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid.

Anti-laminin 332 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by predominant mucosal lesions and autoantibodies against laminin 332. The exact diagnosis of anti-laminin 332 MMP is important since nearly 30% of patients develop solid cancers. This study compared two independently developed diagnostic indirect immunofluorescence (IF) tests based on recombinant laminin 332 expressed in HEK239 cells (biochip mosaic assay) and the migration trails of cultured keratinocytes rich in laminin 332 (footprint assay). The sera of 54 anti-laminin 332 MMP, 35 non-anti-laminin 332 MMP, and 30 pemphigus vulgaris patients as well as 20 healthy blood donors were analyzed blindly and independently. Fifty-two of 54 and 54/54 anti-laminin 332 MMP sera were positive in the biochip mosaic and the footprint assay, respectively. In the 35 non-anti-laminin 332 MMP sera, 3 were positive in both tests and 4 others showed weak reactivity in the footprint assay. In conclusion, both assays are easy to perform, highly sensitive, and specific, which will further facilitate the diagnosis of anti-laminin 332 MMP.

Keratinocyte Binding Assay Identifies Anti-Desmosomal Pemphigus Antibodies Where Other Tests Are Negative.

The serological diagnosis of pemphigus relies on the detection of IgG autoantibodies directed against the epithelial cell surface by indirect immunofluorescence (IIF) on monkey esophagus and against desmoglein 1 (Dsg1) and Dsg3 by ELISA. Although being highly sensitive and specific tools, discrepancies can occur. It is not uncommon that sera testing positive by ELISA give a negative result by IIF and vice versa. This brings diagnostic challenges wherein pemphigus has to be ascertained or ruled out, especially when no biopsy is available. We utilized the ability of anti-Dsg3 and anti-Dsg1 IgG to bind in specific desmosomal patterns to living cells to investigate these discrepancies between IIF and ELISA. Living cultured primary normal human keratinocytes were grown under differentiating conditions to induce adequate expression of Dsg1 and Dsg3, incubated with patient serum for 1 h, and then stained to visualize bound IgG. We investigated two different groups; sera from patients with a positive direct immunofluorescence (DIF) and inconsistent serological findings (n = 43) and sera with positive ELISA or IIF but with negative DIF (n = 60). As positive controls we used 50 sera from patients who fulfilled all diagnostics criteria, and 10 sera from normal human subjects served as negative controls. In the DIF positive group, IgG from 39 of the 43 sera bound to the cells in a desmosomal pattern while in the DIF negative group none of the 60 sera bound to the cells. This shows that for pemphigus patients, ELISA and IIF can be negative while anti-desmosomal antibodies are present and vice versa that ELISA and IIF can be positive in non-pemphigus cases. In absence of a biopsy for DIF, such findings may lead to misdiagnosis.