- An ex-vivo RNA trans-splicing strategy to correct human generalized severe epidermolysis bullosa simplex. [Journal Article]
- BJBr J Dermatol 2018 Aug 12
- CONCLUSIONS: In summary, our data demonstrate that trans-splicing-mediated mRNA therapy is an effective method for the correction of dominantly inherited KRT14 mutations at the transcriptional level. This results in the rescue of the EBS-gen sev phenotype and a stabilization of the epidermis in a xenograft mouse model. This article is protected by copyright. All rights reserved.
- The direct binding of collagen XVII and collagen IV is disrupted by pemphigoid autoantibodies. [Journal Article]
- LILab Invest 2018 Aug 08
- The basement membrane zone (BMZ) is framed by hemidesmosomes and extracellular matrix (ECM) including collagen IV (COL4). Hemidesmosomes are multiprotein complexes that include collagen XVII (COL17)....
The basement membrane zone (BMZ) is framed by hemidesmosomes and extracellular matrix (ECM) including collagen IV (COL4). Hemidesmosomes are multiprotein complexes that include collagen XVII (COL17). BMZ proteins can be targeted in autoimmune subepidermal blistering diseases, e.g., pemphigoid targeting COL17. The blistering mechanisms in pemphigoid have not been fully elucidated, especially in mucous membrane pemphigoid (MMP), which mainly affects the mucosa. In this study, we showed that oral lesions in pemphigoid may be attributed to the inhibition of protein-protein interactions by autoantibodies. Using immunoprecipitation, we revealed that COL17 directly binds to COL4 in normal human keratinocytes and normal human oral keratinocytes. In particular, the C-terminus of COL17 is binding site to COL4 in oral keratinocytes. The precise COL4-binding region on COL17 was determined by protein-protein binding assay to be from amino acid Gly1175 to Asp1340 on the C-terminus. MMP-IgG or mAb recognizing the C-terminus hindered the interaction of COL17 with COL4 in oral keratinocytes. Furthermore, keratinocyte adhesion strength to COL4-coated plates was significantly reduced by the treatment of mAb against the C-terminus. In addition, the inflammatory infiltrates around perilesions were significantly less in MMP compared to BP. These results indicate that pemphigoid IgG targeting the C-terminus plays a pathogenic role in blister formation in the oral mucosa to inhibit protein interactions with less inflammation.
- Expression of Laminin 332 in Vesicant Skin Injury and Wound Repair. [Journal Article]
- CDClin Dermatol (Wilmington) 2018; 2(1)
- Sulfur Mustard (SM) is a potent vesicant or blistering agent. It is a highly reactive bi-functional alkylating agent that cross links proteins, DNA, and other cellular components. Laminin 332 is a he...
Sulfur Mustard (SM) is a potent vesicant or blistering agent. It is a highly reactive bi-functional alkylating agent that cross links proteins, DNA, and other cellular components. Laminin 332 is a heterotrimer glycoprotein and a crucial skin component that attaches the epidermal basal keratinocytes to the dermis. SM wounds histologically appear similar to Epidermolysis Bullosa (EB), human genetic blistering diseases that involve genetic changes in laminin 332. The specific mechanism of action of SM exposure is unknown, but there are several key similarities between vesicant induced cutaneous injury and the Junctional form of EB (JEB) cutaneous injury: 1) Initial alkylation causes blistering similar to JEB; 2) Initial injury is followed by protease activation and prolonged inflammation similar to the chronic inflammation observed in EB; 3) The blister plane is at the level of the lamina lucida in the Basement Membrane Zone (BMZ) for both JEB and SM-induced injury. This suggests that injury induced by vesicants is not unique and probably involves malformation of laminin 332. Understanding the role of laminin 332 in SM induced blisters may provide perspectives for future molecular therapeutic countermeasures against SM exposure.
- The Role of Eosinophils in Bullous Pemphigoid: A Developing Model of Eosinophil Pathogenicity in Mucocutaneous Disease. [Review]
- FMFront Med (Lausanne) 2018; 5:201
- Bullous pemphigoid (BP) is an autoimmune blistering disease which carries a significant mortality and morbidity. While historically BP has been characterized as an IgG driven disease mediated by anti...
Bullous pemphigoid (BP) is an autoimmune blistering disease which carries a significant mortality and morbidity. While historically BP has been characterized as an IgG driven disease mediated by anti-BP180 and BP230 IgG autoantibodies, developments in recent years have further elucidated the role of eosinophils and IgE autoantibodies. In fact, eosinophil infiltration and eosinophilic spongiosis are prominent features in BP. Several observations support a pathogenic role of eosinophils in BP: IL-5, eotaxin, and eosinophil-colony stimulating factor are present in blister fluid; eosinophils line the dermo-epidermal junction (DEJ) in the presence of BP serum, metalloprotease-9 is released by eosinophils at the site of blisters; eosinophil degranulation proteins are found on the affected basement membrane zone as well as in serum corresponding with clinical disease; eosinophil extracellular DNA traps directed against the basement membrane zone are present, IL-5 activated eosinophils cause separation of the DEJ in the presence of BP serum; and eosinophils are the necessary cell required to drive anti-BP180 IgE mediated skin blistering. Still, it is likely that eosinophils contribute to the pathogenesis of BP in numerous other ways that have yet to be explored based on the known biology of eosinophils. We herein will review the role of eosinophils in BP and provide a framework for understanding eosinophil pathogenic mechanisms in mucocutaneous disease.
- TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome. [Journal Article]
- JCIJ Clin Invest 2018 Aug 01; 128(8):3595-3604
- Autosomal dominant hyper IgE syndrome (AD-HIES), or Job's syndrome, is a primary immune deficiency caused by dominant-negative mutations in STAT3. Recurrent Staphylococcus aureus skin abscesses are a...
Autosomal dominant hyper IgE syndrome (AD-HIES), or Job's syndrome, is a primary immune deficiency caused by dominant-negative mutations in STAT3. Recurrent Staphylococcus aureus skin abscesses are a defining feature of this syndrome. A widely held hypothesis that defects in peripheral Th17 differentiation confer this susceptibility has never been directly evaluated. To assess the cutaneous immune response in AD-HIES, we induced suction blisters in healthy volunteers (HVs) and patients with AD-HIES and then challenged the wound with lethally irradiated bacteria. We show that cutaneous production of IL-17A and IL-17F was normal in patients with AD-HIES. Overproduction of TNF-α differentiated the responses in AD-HIES from HVs. This was associated with reduced IL-10 family signaling in blister-infiltrating cells and defective epithelial cell function. Mouse models of AD-HIES recapitulated these aberrant epithelial responses to S. aureus and involved defective epithelial-to-mesenchymal transition (EMT) rather than a failure of bacterial killing. Defective responses in mouse models of AD-HIES and primary keratinocyte cultures from patients with AD-HIES could be reversed by TNF-α blockade and by drugs with reported modulatory effects on EMT. Our results identify these as potential therapeutic approaches in patients with AD-HIES suffering S. aureus infections.
- Morning blisters: cantharidin-related Meloidae burns. [Journal Article]
- JTJ Travel Med 2018 Jul 01; 25(1)
- We report several cases of Meloidae-related blisters in French soldiers deployed to Mali. Blister beetles of the Meloidae family produce cantharidin, a blistering agent, for defensive purposes. These...
We report several cases of Meloidae-related blisters in French soldiers deployed to Mali. Blister beetles of the Meloidae family produce cantharidin, a blistering agent, for defensive purposes. These virtually cosmopolitan Coleoptera can cause significant nuisance to travellers and deployed soldiers especially during the rainy season in the Sahel region.
- Bullous Pemphigoid Associated with Ischemic Cerebrovascular Accident and Dementia: Exclusive Blistering Lesions on the Upper Hemiparetic Limb. [Journal Article]
- ADActa Dermatovenerol Croat 2018; 26(2):179-182
- Bullous pemphigoid (BP) has been associated with neurological disorders (NDs), which has led to the hypothesis that molecular mimicry exists between hemidesmosomal proteins and neuronal peptides. A 7...
Bullous pemphigoid (BP) has been associated with neurological disorders (NDs), which has led to the hypothesis that molecular mimicry exists between hemidesmosomal proteins and neuronal peptides. A 79-year-old hemiparetic woman presented with tense bullae affecting exclusively her right paretic upper limb for three months. Histopathology, taken from the perilesional area, revealed an inflammatory infiltrate with predominant eosinophils. IIF evidenced linear IgG deposition in the epidermal side of the cleavage. ELISA detected circulating anti-BP180 and anti-BP230 autoantibodies. Immunoblotting exhibited unspecific reactivity against the 190-kDa periplakin in normal human epidermal extract. The immunocompromised cutaneous district concept may explain the possible mechanism for the exclusive involvement of the autoimmune blistering disease in lymphedematous hemiparetic upper limb.
- The Value of Type IV Collagen Immunohistochemical Staining in the Differential Diagnosis of Autoimmune Subepidermal Bullous Diseases. [Journal Article]
- ADActa Dermatovenerol Croat 2018; 26(2):133-138
- Autoimmune subepidermal bullous diseases (AISBDs) exhibit various clinical presentations, histological appearances, prognoses, and responses to treatment. Many diagnostic techniques, such as direct i...
Autoimmune subepidermal bullous diseases (AISBDs) exhibit various clinical presentations, histological appearances, prognoses, and responses to treatment. Many diagnostic techniques, such as direct immunofluorescence (IF), indirect salt-split skin IF, and enzyme-linked immunosorbent assays, are used in the differential diagnoses of AISBDs. However, these techniques require fresh frozen tissue, expensive laboratory equipment, and sophisticated laboratory techniques. The purpose of this study was to evaluate the value of type IV collagen immunohistochemical (IHC) staining for the differential diagnosis of AISBDs. Paraffin-embedded blocks of skin biopsies were selected from 28 patients with autoimmune subepidermal bullous diseases. Among these 28 cases, 24 patients exhibited bullous pemphigoid (BP), 2 exhibited epidermolysis bullosa acquisita (EBA), 1 exhibited linear immunoglobulin A dermatosis (LAD), and 1 exhibited bullous systemic lupus erythematosus (BSLE). Sections were stained for type IV collagen and examined to determine the location of type IV collagen in the subepidermal blister. Type IV collagen positivity was observed on the base of the subepidermal blister in patients with BP (24 of 24 cases) and LAD (1 of 1 case). Staining was observed on the roof of the blister in patients with EBA (2 of 2 cases) and BSLE (1 of 1 case), and irregular staining was also observed on the base in patients with EBA. In conclusion, type IV collagen IHC staining is a simple and useful diagnostic technique for the differential diagnosis of AISBDs.
- Clinical and Demographic Characteristics of Pemphigus Vulgaris Patients. [Journal Article]
- ADActa Dermatovenerol Croat 2018; 26(2):119-125
- Pemphigus is an autoimmune disease characterized by intraepithelial bullae and erosions in the skin and mucosa. We aimed to evaluate the clinical and demographic characteristics of pemphigus vulgaris...
Pemphigus is an autoimmune disease characterized by intraepithelial bullae and erosions in the skin and mucosa. We aimed to evaluate the clinical and demographic characteristics of pemphigus vulgaris (PV) patients who presented to our Department. Patients who presented to our Department between May 2013 and May 2014, were examined dermatologically and diagnosed with PV based on clinical, histological and direct immunofluorescent findings. Name, family name, and gender of the patients, their complaint at presentation, onset time and location of the lesions, the number of lesions, systemic treatments received by patients and patients' medication histories were recorded. Forty-nine PV patients were included in our study. Among these, 22 (44.9%) were female and 27 (55.1%) male. The mean age of the patients was 53.28±14.70 (range 23 to 79) years. The mean duration of the disease was 44.45±45.68 (range 1 to 180) months. The most common complaints at presentation were lesion in the mouth (47/49) and lesion/blister in the skin (39/49). The onset locations of the lesions were the oropharynx (63.3%), the skin and oropharynx combined (16.3%), the skin (18.4%) and the anus (2%). The chronological order for the sites of involvement were as follows: first the oropharynx then the skin (42.9%), first the skin then the oropharynx (18.4%), and the oropharynx and the skin combined (16.3%). Ten patients (20.4%) had mucosal involvement and one (2%) had skin involvement alone, whereas both mucosal and skin involvements were observed in 38 patients (77.6%). Forty-seven patients (95.9%) had not used any medications that could have led to pemphigus. One patient had a history of beta-blocker use and another had a history of ACE inhibitor prior to the emergence of the pemphigus lesions. The clinical and demographic results of the PV patients in our region were consistent with those from other studies.
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- A Case of Bullous Pemphigoid: A Prevalent and Potentially Fatal Condition. [Journal Article]
- CCureus 2018 Apr 25; 10(4):e2533
- Bullous pemphigoid is the most common of the blistering disorders. It is most commonly found in the elderly and is diagnosed based on clinical, histologic, and immunologic criteria. It presents clini...
Bullous pemphigoid is the most common of the blistering disorders. It is most commonly found in the elderly and is diagnosed based on clinical, histologic, and immunologic criteria. It presents clinically with diffuse eczematous, pruritic, urticaria-like lesions, with the later appearance of tense bullae or blistering lesions typically filled with clear fluid. Histologically, a sub-epidermal blister is seen and immunofluorescence shows immunoglobulin G antibodies directed against the structural components of the keratinocytic hemidesmosomal proteins BP180 and BP230. Multiple treatment modalities are present for this condition, including anti-inflammatory medications, medications that reduce antibody formation, and treatments to increase the elimination of antibodies. The aim of this case report is to present a classic case of this condition, to highlight an awareness of differing treatment options, and to advocate referral to a dermatologist given its potential severity.