Cytokine profiling reveals HLA-linked Th2 and Th17 driven immune activation in pemphigus vulgaris patients and genetically susceptible healthy controls.

Introduction: Cytokines and chemokines direct the inflammatory response and may serve as markers of immune dysregulation in Pemphigus vulgaris (PV), an autoimmune blistering skin disorder. Previous studies on limited numbers of patients and cytokine profiles in PV have produced equivocal results regarding the role these mediators play in disease.

Methods: In this study, we interrogated serum samples from 116 PV patients and 29 healthy controls by multiplexed bead array assays across a comprehensive set of cytokines and chemokines covering several functional categories, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, IL-21, IL-22, IL-23, TNFα, IFNγ, MCP-1, and Eotaxin.

Data-Driven Image Analysis to Determine Antibody-Induced Dissociation of Cell-Cell Adhesion and Antibody Pathogenicity in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is a blistering autoimmune disease that affects the skin and mucous membranes. The precise mechanisms by which PV antibodies induce a complete loss of cohesion of keratinocytes are not fully understood. But it is accepted that the process starts with antibody binding to desmosomal targets which leads to its disassembly and subsequent structural changes to cell-cell adhesions.

Desmosomal Cadherin Tension Loss in Pemphigus Vulgaris Mediated by the Inhibition of Active RhoA at Cell-Cell Adhesions.

Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity.

Inheritance-Specific Dysregulation of Th1- and Th17-Associated Cytokines in Alopecia Areata.

Autoimmune diseases tend to cluster in families, suggesting genetic predisposition to autoimmunity associated with familial background. We have previously reported similarities in gene expression patterns and PTPN22 polymorphisms between alopecia areata (AA) patients and their healthy relatives, but not unrelated healthy controls. However, the spectrum of disease promoting (or preventing) pathways that may be activated in blood relatives of AA patients remains to be defined.

Worldwide epidemiologic factors in pemphigus vulgaris and bullous pemphigoid.

Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging.

Patient genetics shape the autoimmune response in the blistering skin disease pemphigus vulgaris.

Background And Aim: Pemphigus vulgaris (PV) is known to have one of the strongest HLA associations among autoimmune diseases. DRB1*0402 and DQB1*0503 in particular are significantly overrepresented in PV patients in certain worldwide populations. Yet, there remain significant gaps in our understanding regarding the precise link between PV-associated HLA molecules, the specificity of the autoimmune response, and clinical expression.

Desmoglein compensation hypothesis fidelity assessment in Pemphigus.

The pemphigus group of autoimmune blistering diseases encompasses pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Lesion location in pemphigus has been elegantly postulated by the Desmoglein Compensation Hypothesis (DCH), which references the distribution of desmoglein (Dsg) proteins in the epidermis along with a patient's autoantibody profile to describe three different lesion phenotypes: PF is characterized by subcorneal lesions in the presence of anti-Dsg1 antibodies only, while lesions in PV are suprabasilar and accompanied by anti-Dsg3 antibodies only in mucosal PV, or both anti-Dsg3 and anti-Dsg1 in the case of mucocutaneous PV. While the validity of this hypothesis has been supported by several studies and is prominently featured in textbooks of dermatology, a number of logical inconsistencies have been noted and exceptions have been published in several small-scale studies.

Case report: Documentation of cutaneous only pemphigus vulgaris without history of mucosal lesions in North America.

Background: Pemphigus is a group of autoimmune blistering diseases including Pemphigus vulgaris (PV) and Pemphigus foliaceus (PF). These conditions exhibit lesions with mucosal or mucocutaneous (PV) or cutaneous (PF) morphology, as framed by the Desmoglein Compensation Hypothesis (DCH). However, some PV patients present with solely cutaneous disease (cPV), and growing evidence suggests the existence of a cPV subtype of mucosal erosions/blisters (cPVwohm), neither of which are predicted by the DCH.

Evolutionary context of psoriatic immune skin response.

The skin is vital for protecting the body and perceiving external stimuli in the environment. Ability to adapt between environments is in part based on skin phenotypic plasticity, indicating evolved homeostasis between skin and environment. This homeostasis reflects the greater relationship between the body and the environment, and disruptions in this balance may lead to accumulation of susceptibility factors for autoimmune conditions like psoriasis.

Modulation of Mechanical Stress Mitigates Anti-Dsg3 Antibody-Induced Dissociation of Cell-Cell Adhesion.

It is becoming increasingly clear that mechanical stress in adhesive junctions plays a significant role in dictating the fate of cell-cell attachment under physiological conditions. Targeted disruption of cell-cell junctions leads to multiple pathological conditions, among them the life-threatening autoimmune blistering disease pemphigus vulgaris (PV). The dissociation of cell-cell junctions by autoantibodies is the hallmark of PV, however, the detailed mechanisms that result in tissue destruction remain unclear.

A Retrospective Study of Patient-Reported Data of Bullous Pemphigoid and Mucous Membrane Pemphigoid From a US-Based Registry.

Bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare chronic autoimmune disorders characterized by subepidermal blistering. For the United States, there is a limited amount of studies in BP and MMP that address disease demographics and clinical data. In order to more comprehensively examine disease demographics and clinical factors, we performed a retrospective analysis of patient-reported data of 138 BP and 165 MMP patients enrolled in the International Pemphigus & Pemphigoid Foundation (IPPF) disease registry from 2010-2016.

Single-cell membrane drug delivery using porous pen nanodeposition.

Delivering molecules onto the plasma membrane of single cells is still a challenging task in profiling cell signaling pathways with single cell resolution. We demonstrated that a large quantity of molecules could be targeted and released onto the membrane of individual cells to trigger signaling responses. This is achieved by a porous pen nanodeposition (PPN) method, in which a multilayer porous structure, serving as a reservoir for a large amount of molecules, is formed on an atomic force microscope (AFM) tip using layer-by-layer assembly and post processing.

Anti-Thyroid Peroxidase Reactivity Is Heightened in Pemphigus Vulgaris and Is Driven by Human Leukocyte Antigen Status and the Absence of Desmoglein Reactivity.

Pemphigus vulgaris (PV) belongs to an autoimmune disease cluster that includes autoimmune thyroid disease (AITD), suggesting common mechanisms driving autoimmune susceptibility. Our group has shown that PV patients exhibit significant reactivity to AITD-related anti-thyroid peroxidase (anti-TPO), and anti-TPO antibodies affect signaling pathways in keratinocytes similar to anti-desmoglein (Dsg) 3 antibodies. To further assess the relevance of anti-TPO reactivity in PV, we analyzed anti-TPO levels in 280 PV and 167 healthy control serum samples across a comprehensive set of variable and static parameters of disease activity and etiopathogenesis.

Longitudinal Tracking of Autoantibody Levels in a Pemphigus Vulgaris Patient: Support for a Role of Anti-Desmoglein 1 Autoantibodies as Predictors of Disease Progression.

Anti-desmoglein (Dsg) 1 and -Dsg3 antibody titers have an established role in the diagnosis of the autoimmune blistering skin disease pemphigus vulgaris (PV). However, their usefulness for disease monitoring has been controversial. A recent large-scale immunoprofiling study by our group indicated that anti-Dsg1 levels may be a better predictor of disease activity than anti-Dsg3 levels, with declining levels predicting progression from active phase of disease to early remission, irrespective of lesional subtypes.

Positive correlation of anti-herpes simplex type I virus antibody levels with pemphigus vulgaris disease status and activity in a large patient cohort.

It is well accepted that pemphigus vulgaris (PV) is genetically linked to specific HLA class II subtypes. Environmental factors, including the role of herpes simplex virus (HSV1) in disease manifestation, have also been implicated, but in a limited number of patients and with inconsistent results. To clarify an association between HSV1 and PV in a large data set, including a stratification by dynamic and static clinical parameters, including disease activity, therapy status, HLA association, and gender.

Increased oxidative stress in pemphigus vulgaris is related to disease activity and HLA-association.

Pemphigus vulgaris (PV) is a rare blistering skin disorder characterized by the disadhesion of keratinocytes due to autoantibody attack against epidermal targets including desmoglein (Dsg) 3, Dsg 1 and possibly other adhesion and non-adhesion molecules. The mechanisms leading to immune-mediated pathology in PV are multifactorial and not fully understood. Recently, oxidative stress (antioxidant/oxidant disequilibrium) has been proposed as a contributory mechanism of autoimmune skin diseases, including PV.

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus.

Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease.

Evaluation of a Newly Available ELISA for Envoplakin Autoantibodies for the Diagnosis of Paraneoplastic Pemphigus.

Importance: Paraneoplastic pemphigus (PNP) is routinely diagnosed by the presence of autoantibodies for desmoplakin by indirect immunofluorescence (IIF) on rat bladder epithelium (RBE). IIF on RBE has recently been found to be positive in select cases of other blistering disorders. A new ELISA that detects envoplakin autoantibodies has recently been developed for the diagnosis of PNP.

Cellular level robotic surgery: Nanodissection of intermediate filaments in live keratinocytes.

We present the nanosurgery on the cytoskeleton of live cells using AFM based nanorobotics to achieve adhesiolysis and mimic the effect of pathophysiological modulation of intercellular adhesion. Nanosurgery successfully severs the intermediate filament bundles and disrupts cell-cell adhesion similar to the desmosomal protein disassembly in autoimmune disease, or the cationic modulation of desmosome formation. Our nanomechanical analysis revealed that adhesion loss results in a decrease in cellular stiffness in both cases of biochemical modulation of the desmosome junctions and mechanical disruption of intercellular adhesion, supporting the notion that intercellular adhesion through intermediate filaments anchors the cell structure as focal adhesion does and that intermediate filaments are integral components in cell mechanical integrity.

Nanorobotic investigation identifies novel visual, structural and functional correlates of autoimmune pathology in a blistering skin disease model.

There remain major gaps in our knowledge regarding the detailed mechanisms by which autoantibodies mediate damage at the tissue level. We have undertaken novel strategies at the interface of engineering and clinical medicine to integrate nanoscale visual and structural data using nanorobotic atomic force microscopy with cell functional analyses to reveal previously unattainable details of autoimmune processes in real-time. Pemphigus vulgaris is a life-threatening autoimmune blistering skin condition in which there is disruption of desmosomal cell-cell adhesion structures that are associated with the presence of antibodies directed against specific epithelial proteins including Desmoglein (Dsg) 3.

Non-melanoma skin cancer and NSAID use in women with a history of skin cancer in the Women's Health Initiative.

Objective: Evidence for the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on non-melanoma skin cancer (NMSC) risk is inconsistent. We prospectively examined whether regular, inconsistent, or no/low-use of NSAIDs is associated with lower NMSC risk among 54,728 postmenopausal Caucasian women in the Women's Health Initiative Observational Study enrolled between 1993 and 1998.

Methods: Logistic regression models were used to assess odds of NMSC after adjusting for skin type, sun exposure history and indication for NSAID use.

Gender differences in alopecia areata.

Alopecia areata (AA) is a common, non-scarring, autoimmune hair-loss disorder with a complex genetic and environmental etiology. A higher incidence rate of AA in the female population is well described. It is unclear why females are more likely to be diagnosed with AA and what, if any, differences in disease phenotype exist between males and females.