The Genetics of Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by auto-antibodies (auto-Abs) directed against epithelial desmosomal components and leading to disruption of cell-cell adhesion. The exact mechanisms underlying the disease pathogenesis remain unknown and treatment is still based on immunosuppressive drugs, such as corticosteroids, which are associated with potentially significant side effects. Ethnic susceptibility, familial occurrence, and autoimmune comorbidity, suggest a genetic component to the pathogenesis of the disease, which, if discovered, could advance our understanding of PV pathogenesis and thereby point to novel therapeutic targets for this life-threatening disorder. In this article, we review the evidence for a genetic basis of PV, summarize the different approaches used to investigate susceptibility traits for the disease and describe past and recent discoveries regarding genes associated with PV, most of which belong to the human leukocyte antigen (HLA) locus with limited data regarding association of non-HLA genes with the disease

Mycosis Fungoides Associated with Kaposi\u27s Sarcoma, T-cell Rich B-cell Lymphoma, and T cell Lymphoma with Angioimmunoblastic Features

A patient with mycosis fungoides (MF), Kaposi\u27s sarcoma, T-cell B-cell rich lymphoma and T-cell lymphoma with angioimmunoblastic features is described. The appearance of multiple malignancies in this patient may have been caused by previous exposure to radiation in the Chernobyl accident and/or systemic chemotherapy for the initial T-cell B-cell rich lymphoma which he underwent.</p

Loss of SNAP29 Impairs Endocytic Recycling and Cell Motility

Intracellular membrane trafficking depends on the ordered formation and consumption of transport intermediates and requires that membranes fuse with each other in a tightly regulated and highly specific manner. Membrane anchored SNAREs assemble into SNARE complexes that bring membranes together to promote fusion. SNAP29 is a ubiquitous synaptosomal-associated SNARE protein. It interacts with several syntaxins and with the EH domain containing protein EHD1. Loss of functional SNAP29 results in CEDNIK syndrome (Cerebral Dysgenesis, Neuropathy, Ichthyosis and Keratoderma). Using fibroblast cell lines derived from CEDNIK patients, we show that SNAP29 mediates endocytic recycling of transferrin and β1-integrin. Impaired β1-integrin recycling affected cell motility, as reflected by changes in cell spreading and wound healing. No major changes were detected in exocytosis of VSVG protein from the Golgi apparatus, although the Golgi system acquired a dispersed morphology in SNAP29 deficient cells. Our results emphasize the importance of SNAP29 mediated membrane fusion in endocytic recycling and consequently, in cell motility

An Uncommon Presentation of Darier-White Disease with Hystrix-like Palmoplantar Keratoderma

Darier-White disease is a relatively common autosomal dominant genodermatosis caused by mutation in the ATP2A2 gene. It is characterized by multiple warty papules coalescing into plaques in the seborrheic areas and by specific histological skin changes. Palm and sole involvement in Darier-White disease is usually mild, mainly featuring discrete and small keratotic papules. We present a unique case of Darier-White disease presenting with a diffuse, mutilating hystrix-like palmoplantar keratoderma

An Uncommon Presentation of Darier-White Disease with Hystrix-like Palmoplantar Keratoderma

Darier-White disease is a relatively common autosomal dominant genodermatosis caused by mutation in the ATP2A2 gene. It is characterized by multiple warty papules coalescing into plaques in the seborrheic areas and by specific histological skin changes. Palm and sole involvement in Darier-White disease is usually mild, mainly featuring discrete and small keratotic papules. We present a unique case of Darier-White disease presenting with a diffuse, mutilating hystrix-like palmoplantar keratoderma

CRP Levels as a Prognostic Factor in Mycosis Fungoides

Mycosis Fungoides (MF) and Sézary syndrome (SS) are the most com- mon forms of cutaneous T-cell lymphomas. Few validated prognostic factors have been reported in MF/SS, especially when compared with non-cutaneous lympho- mas. Increased C-reactive protein (CRP) levels have recently been associated with poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of serum CRP levels at diagnosis in patients with MF/ SS. This retrospective study included 76 patients with MF/SS. Stage was assigned according to the ISCL/EORTC guidelines. The follow-up period was 24 months or more. Disease course and response to treatment were determined using quantita- tive scales. Wilcoxon’s rank test and multivariate regression analysis were used to analyze the data. Increased CRP levels correlated significantly with advanced stages (Wilcoxon’s test, P>0.0001). Furthermore, increased CRP levels were associated with a lower treatment response rate (Wilcoxon’s test, P=0.0012). Multivariate regression analysis showed that CRP is an independent predictor of advanced clinical stage at diagnosis.The present data suggest that elevated CRP levels could serve as a useful prognostic factor in MF/SS and may assist in guiding treatment choices

CRP Levels as a Prognostic Factor in Mycosis Fungoides

Mycosis Fungoides (MF) and Sézary syndrome (SS) are the most com- mon forms of cutaneous T-cell lymphomas. Few validated prognostic factors have been reported in MF/SS, especially when compared with non-cutaneous lympho- mas. Increased C-reactive protein (CRP) levels have recently been associated with poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of serum CRP levels at diagnosis in patients with MF/ SS. This retrospective study included 76 patients with MF/SS. Stage was assigned according to the ISCL/EORTC guidelines. The follow-up period was 24 months or more. Disease course and response to treatment were determined using quantita- tive scales. Wilcoxon’s rank test and multivariate regression analysis were used to analyze the data. Increased CRP levels correlated significantly with advanced stages (Wilcoxon’s test, P>0.0001). Furthermore, increased CRP levels were associated with a lower treatment response rate (Wilcoxon’s test, P=0.0012). Multivariate regression analysis showed that CRP is an independent predictor of advanced clinical stage at diagnosis.The present data suggest that elevated CRP levels could serve as a useful prognostic factor in MF/SS and may assist in guiding treatment choices

ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation

Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1α, IL-6, TNFα, and IFN-γ was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1α and IL-6 was enhanced in some experiments but not in others whereas release of TNF-α dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling

Insulin-Like Growth Factor-Binding Protein 7 Regulates Keratinocyte Proliferation, Differentiation and Apoptosis

Insulin-like growth factor (IGF)-binding protein 7 (IGFBP7) belongs to the IGFBP superfamily, which is involved in the regulation of IGF and insulin signaling. Recently, a global gene expression study revealed that IGFBP7 is downregulated in the psoriatic epidermis, with UVB phototherapy restoring its expression to normal. In the present study, we confirmed that IGFBP7 expression is decreased in psoriatic lesions. Given the previous data suggesting a role for IGFBP7 in the control of cancer cell growth, we investigated its involvement in the regulation of keratinocyte (KC) proliferation and differentiation, which are abnormal in psoriasis. To model IGFBP7 downregulation in vitro, we used IGFBP7-specific small interfering RNA or small hairpin RNA-expressing lentiviral vectors in HaCaT cells or primary human KCs. Downregulation of IGFBP7 was found to markedly enhance KC proliferation in both systems, was associated with a significant decrease in KC susceptibility to tumor necrosis factor-α-induced apoptosis, but did not affect senescence. Downregulation of IGFBP7 was also shown to block expression of genes associated with calcium-induced differentiation of human KCs. Finally, recombinant IGFBP7 was found to inhibit KC proliferation and enhanced their apoptosis. These data position IGFBP7 as a regulator of KC proliferation and differentiation, suggesting a potential role for this protein in the pathophysiology and treatment of hyperproliferative dermatoses such as psoriasis