Pemphigus foliaceus je poměrně vzácným onemocněním patřícím mezi bulózní dermatózy skupiny pemphigu. Jedná se skupinu autoimunitních kožních onemocnění, kde patofyziologickým mechanismem jejich vzniku je tvorba autoprotilátek proti proteinům ve struktuře desmozomů keratinocytů. Dle typu protilátek se jednotlivé subtypy pemphigu manifestují na kůži, sliznicích, nebo v obou lokalizacích současně. Klinické projevy jednotlivých subtypů mají svoji typickou morfu i predilekční lokalizaci, které společně s komplexním histopatologickým a zejména imunofluorescenčním vyšetřením nabízí poměrně přesnou diagnostiku onemocnění. Autorka popisuje případ pacientky s typickými projevy pemphigus foliaceus úspěšně léčené konvenčními imunosupresivy s výbornou terapeutickou odpovědí.

Pemphigus foliaceus is relatively rare subtype of pemphigus, grouped within the mucocutaneous bullous diseases. These autoimmune blistering disorders are characterized by the presence of circulating antibodies against desmogleins, in structure of epidermal intercellular adhesions. Depending on the subtype of antibody present, these diseases can manifest with mucosal, mucocutaneous, or cutaneous presentation. Clinical manifestation and localization of skin lesions are unique for each of the subtypes of pemphigus, which, supported by histopathological findings and direct immunofluorescence, provide accurate diagnostic conclusion. In this case-report, author describes typical case of pemphigus foliaceus, successfully treated by immunosuppressants with great therapeutical outcome.

• MeSH
• Adrenal Cortex Hormones administration & dosage   therapeutic use   MeSH
• Immunosuppressive Agents administration & dosage   therapeutic use   MeSH
• Humans MeSH
• Pemphigus * diagnosis   drug therapy   MeSH
• Aged MeSH
• Skin Diseases, Vesiculobullous diagnosis   drug therapy   MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Pemphigus Vulgaris (PV) is a life-threatening autoimmune disease manifested with blisters in the skin and mucosa and caused by autoantibodies against adhesion protein desmoglein-3 (Dsg3) expressed in epithelial membrane linings of these tissues. Despite many studies, the pathogenesis of PV remains incompletely understood. Recently we have shown Dsg3 plays a role in regulating the yes-associated protein (YAP), a co-transcription factor and mechanical sensor, and constraining reactive oxygen species (ROS). This study investigated the effect of PV sera as well as the anti-Dsg3 antibody AK23 on these molecules. We detected elevated YAP steady-state protein levels in PV cells surrounding blisters and perilesional regions and in keratinocytes treated with PV sera and AK23 with concomitant transient ROS overproduction. Cells treated with hydrogen peroxide also exhibited augmented nuclear YAP accompanied by reduction of Dsg3 and α-catenin, a negative regulator of YAP. As expected, transfection of α-catenin-GFP plasmid rendered YAP export from the nucleus evoked by hydrogen peroxide. In addition, suppression of total YAP was observed in hydrogen peroxide treated cells exposed to antioxidants with enhanced cell-cell adhesion being confirmed by decreased fragmentation in the dispase assay compared to hydrogen peroxide treatment alone. On the other hand, the expression of exogenous YAP disrupted intercellular junction assembly. In contrast, YAP depletion resulted in an inverse effect with augmented expression of junction assembly proteins, including Dsg3 and α-catenin capable of abolishing the effect of AK23 on Dsg3 expression. Finally, inhibition of other kinase pathways, including p38MAPK, also demonstrated suppression of YAP induced by hydrogen peroxide. Furthermore, antioxidant treatment of keratinocytes suppressed PV sera-induced total YAP accumulation. In conclusion, this study suggests that oxidative stress coupled with YAP dysregulation attributes to PV blistering, implying antioxidants may be beneficial in the treatment of PV.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   metabolism   MeSH
• alpha Catenin metabolism   MeSH
• Antioxidants pharmacology   therapeutic use   MeSH
• Autoantibodies blood   immunology   metabolism   MeSH
• Cell Adhesion drug effects   immunology   MeSH
• Cell Line MeSH
• Desmoglein 3 immunology   metabolism   MeSH
• Gene Knockdown Techniques MeSH
• Keratinocytes MeSH
• Humans MeSH
• MAP Kinase Signaling System drug effects   immunology   MeSH
• Oxidative Stress drug effects   immunology   MeSH
• Pemphigus blood   drug therapy   immunology   pathology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Case-Control Studies MeSH
• Transcription Factors genetics   metabolism   MeSH
• Mouth Mucosa immunology   pathology   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH

To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Methods: Phospholipid-poly(lactic-co-glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. Results: The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Conclusions: Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.

• MeSH
• Bridged Bicyclo Compounds, Heterocyclic administration & dosage   pharmacology   MeSH
• HaCaT Cells MeSH
• Chemokine CXCL1 drug effects   immunology   MeSH
• Chemokine CXCL2 drug effects   immunology   MeSH
• Chemotaxis drug effects   MeSH
• Desmoglein 3 immunology   MeSH
• Epidermis MeSH
• Phospholipids * MeSH
• Immunoconjugates pharmacology   MeSH
• Phosphodiesterase 4 Inhibitors administration & dosage   pharmacology   MeSH
• Keratinocytes drug effects   immunology   MeSH
• Polylactic Acid-Polyglycolic Acid Copolymer * MeSH
• Drug Delivery Systems MeSH
• Humans MeSH
• Lysosomes metabolism   ultrastructure   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Nanoparticles * MeSH
• Neutrophils drug effects   MeSH
• Drug Carriers MeSH
• Antibodies immunology   MeSH
• Psoriasis immunology   pathology   MeSH
• Boron Compounds administration & dosage   pharmacology   MeSH
• Hair Follicle MeSH
• Inflammation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Autoři popisují případ 18letého pacienta trpícího pemphigus vulgaris, u kterého pro protrahovaný průběh léčby, četné exacerbace onemocnění, rozvoj komplikací v rámci dlouhodobé kortikoterapie a neúčinnost předchozí adjuvantní terapie (azathioprin, cyklofosmamid, mykofenolát mofetil), byla zahájena adjuvantní terapie rituximabem. V současné době je popisovaný pacient již 21 měsíců v kompletní remisi onemocnění, jen s podpůrnou terapií osteoporózy. Rituximab je chimérická (myší/lidská) monoklonální protilátka namířená proti povrchovému receptoru CD20 B-lymfocytů, která je nově indikována v první linii celkové terapie pemfigu a která v klinických studiích prokázala dobrou terapeutickou odpověď a steroidy šetřící efekt. Autoři předkládají přehled současných poznatků o léčbě tohoto onemocnění rituximabem.

The authors describes a case of a 18-year-old patient suffering from pemphigus vulgaris in whom adjuvant therapy with rituximab has been initiated due to the protracted course of treatment, frequent exacerbations of the disease, development of multiple complications during long-term systemic corticosteroid therapy and ineffective prior adjuvant therapy (azathioprine, cyclophosphamide, mycophenolate mofetil). Currently, the described patient has been in complete remission of the disease for 21 months only with supportive osteoporosis therapy. Rituximab is a chimeric (murine/human) mono-clonal antibody targeting B cell surface receptor CD20 and has been newly introduced to the first line of systemic therapy of pemphigus and induced good therapeutic response and steroid-sparing effect in clinical trials. The authors present an overview of current knowledge about the treatment of this disease with rituximab.

• Keywords
• CD19 pozitivní B-lymfocyty,
• MeSH
• Desmoglein 1 MeSH
• Desmoglein 3 MeSH
• Adrenal Cortex Hormones adverse effects   MeSH
• Humans MeSH
• Adolescent MeSH
• Osteoporosis etiology   therapy   MeSH
• Pemphigus * therapy   MeSH
• Rituximab therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

BACKGROUND: The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence. METHODS: Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence-positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lübeck. RESULTS: In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic. LIMITATIONS: Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic. CONCLUSIONS: The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD.

• MeSH
• Autoimmune Diseases blood   diagnosis   MeSH
• Pemphigoid, Bullous blood   diagnosis   immunology   MeSH
• Child MeSH
• Adult MeSH
• Fluorescent Antibody Technique, Indirect methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Pemphigus blood   diagnosis   immunology   MeSH
• Prospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell-cell adhesion and regulates various signaling pathways involved in the progression and metastasis of cancer where it is upregulated. We show here that expression of Dsg3 impacts on the expression and function of p53, a key transcription factor governing the responses to cellular stress. Dsg3 depletion increased p53 expression and activity, an effect enhanced by treating cells with UVB, mechanical stress and genotoxic drugs, whilst increased Dsg3 expression resulted in the opposite effects. Such a pathway in the negative regulation of p53 by Dsg3 was Dsg3 specific since neither E-cadherin nor desmoplakin knockdown caused similar effects. Analysis of Dsg3-/- mouse skin also indicated an increase of p53/p21WAF1/CIP1 and cleaved caspase-3 relative to Dsg3+/- controls. Finally, we evaluated whether this pathway was operational in the autoimmune disease PV in which Dsg3 serves as a major antigen involved in blistering pathogenesis. We uncovered increased p53 with diffuse cytoplasmic and/or nuclear staining in the oral mucosa of patients, including cells surrounding blisters and the pre-lesional regions. This finding was verified by in vitro studies where treatment of keratinocytes with PV sera, as well as a characterized pathogenic antibody specifically targeting Dsg3, evoked pronounced p53 expression and activity accompanied by disruption of cell-cell adhesion. Collectively, our findings suggest a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, and this pathway is disrupted in PV.

• MeSH
• Desmoglein 3 deficiency   metabolism   MeSH
• Desmosomes metabolism   MeSH
• Stress, Physiological * MeSH
• Caspase 3 metabolism   MeSH
• Keratinocytes metabolism   MeSH
• Cells, Cultured MeSH
• Skin metabolism   MeSH
• Leupeptins pharmacology   MeSH
• Humans MeSH
• Mice MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Pemphigus blood   immunology   pathology   MeSH
• Proteolysis MeSH
• Antibodies immunology   MeSH
• Dogs MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Dogs MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Antigens, CD20 administration & dosage   adverse effects   therapeutic use   MeSH
• Apoptosis genetics   immunology   drug effects   MeSH
• Biological Therapy MeSH
• Dermatology methods   trends   MeSH
• Desmogleins isolation & purification   MeSH
• Phagocytosis genetics   immunology   drug effects   MeSH
• Financing, Organized MeSH
• Infections drug therapy   complications   MeSH
• Immunoglobulins, Intravenous administration & dosage   adverse effects   therapeutic use   MeSH
• Infusions, Intravenous methods   utilization   MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Antibodies, Monoclonal administration & dosage   adverse effects   therapeutic use   MeSH
• Pemphigus drug therapy   complications   MeSH
• Disease Progression MeSH
• Sepsis drug therapy   complications   MeSH
• Statistics as Topic MeSH
• Outcome and Process Assessment, Health Care MeSH
• Check Tag
• Humans MeSH

The human lectin galectin-3 is a multifunctional effector with special functions in regulation of adhesion and apoptosis. Its unique trimodular organization includes the 12-residue N-terminal sequence, a substrate for protein kinase CK1-dependent phosphorylation. As a step towards elucidating its significance, we prepared phosphorylated galectin-3, labelled it and used it as a tool in histochemistry. We monitored normal and malignant squamous epithelia. Binding was suprabasal with obvious positive correlation to the degree of differentiation and negative correlation to proliferation. The staining pattern resembled that obtained with the unmodified lectin. Basal cell carcinomas were invariably negative. The epidermal positivity profile was akin to distribution of the desmosomal protein desmoglein, as also seen with keratinocytes in vitro. In all cases, binding was inhibitable by the presence of lactose, prompting further investigation of the activity of the lectin site by a sensitive biochemical method, i.e. isothermal titration calorimetry. The overall affinity and the individual enthalpic and entropic contributions were determined. No effect of phosphorylation was revealed. This strategic combination of histo- and biochemical techniques applied to an endogenous effector after its processing by a protein kinase thus enabled a detailed monitoring of the binding properties of the post-translationally modified lectin. It underscores the value of using endogenous lectins as a histochemical tool. The documented approach has merit for applications beyond lectinology.

• MeSH
• Staining and Labeling MeSH
• Epithelium chemistry   metabolism   pathology   MeSH
• Epithelial Cells cytology   chemistry   MeSH
• Financing, Organized MeSH
• Phosphorylation MeSH
• Galectin 3 metabolism   MeSH
• Immunohistochemistry MeSH
• Calorimetry MeSH
• Humans MeSH
• Protein Processing, Post-Translational MeSH
• Neoplasms, Squamous Cell chemistry   microbiology   pathology   MeSH
• Binding Sites MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH