Pemphigus & Pemphigoid
Recent Advances in Understanding Pemphigus and Bullous Pemphigoid
For many years, The Journal of Investigative Dermatology (JID) has been a leader in our understanding of many aspects of the major autoimmune blistering skin diseases, pemphigus and bullous pemphigoid. The purpose of this review is to highlight and summarize those advances by discussing the respective articles, published in the JID from 2015 to 2019. Seminal articles from elsewhere in the literature that set the stage for those advances, or that are “classics” in the area, are also included to provide context and a more complete picture.Gliptin-Associated Bullous Pemphigoid: A Valuable Model of the Mechanism of Breakdown of Immune Tolerance against BP180
The study by Plaquevent et al. strongly supports the recent discovery that the use of gliptins is a risk factor for bullous pemphigoid (BP). However, regarding the phenotype of gliptin-associated BP and the necessity of gliptin withdrawal, clinical data remain scarce. We predict that future studies of gliptin-associated BP will offer valuable information concerning autoimmunity against BP180 and may also shed light on the pathology of autoimmune diseases in general.Demographics and Autoantibody Profiles of Pemphigoid Patients with Underlying Neurologic Diseases
Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion molecules, known as BP180 and BP230. Homologues to these proteins are found in the brain, and it is hypothesized that neurologic disease leads to the production of autoantibodies that can cross-react with their cutaneous forms. To better understand the link between BP and neurologic disease, we evaluated primary demographic features (age, sex, race, ethnicity, and elapsed time between onset of skin symptoms and BP diagnosis), severity of BP, and IgG and IgE autoantibody levels in BP control individuals and patients with BP with preceding Parkinson disease, dementia, and stroke.Desmoglein 1 Deficiency Causes Lethal Skin Blistering
Pemphigus is an autoimmune bullous disorder affecting both mucous membranes and the epidermis (Kasperkiewicz et al., 2017). It is widely accepted that pemphigus is caused by autoantibodies primarily targeting desmosomal cadherins desmoglein (Dsg)1 and 3, which are crucial for intercellular cohesion of keratinocytes. The relevance of autoantibodies against other antigens detectable in pemphigus patients is unclear yet (Spindler et al., 2018). There are two main forms of pemphigus, which differ with respect to their clinical phenotype: in pemphigus vulgaris, skin blistering affects the deep epidermis when, in addition to antibodies against Dsg3, autoantibodies targeting Dsg1 are detectable (Spindler and Waschke, 2018).Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population
Dipeptidyl peptidase-4 inhibitors have been suspected to induce bullous pemphigoid (BP). The objective of this study was to compare the observed frequency of gliptin intake in a large sample of 1,787 BP patients diagnosed between 2012 and 2015 in France, with the expected frequency after indirect age standardization on 225,412 individuals extracted from the database of the National Healthcare Insurance Agency. The secondary objective was to assess the clinical characteristics and the course of gliptin-associated BP, depending on whether gliptin was continued or stopped.A Homozygous Nonsense Mutation in the DSG3 Gene Causes Acantholytic Blisters in the Oral and Laryngeal Mucosa
Keratinocytes bind to adjacent keratinocytes via desmosomes. Desmosomal cadherins, the transmembrane proteins of desmosomes, consist of four types of desmogleins (DSG1–4) and three types of desmocollins (DSC1–3), which form heterodimers or homodimers in the intercellular space (Delva et al., 2009). Among them, DSG1 is expressed throughout the skin epidermis, whereas DSG3 is expressed predominantly in the basal layer. In the mucosal epithelium, however, little DSG1 is expressed, whereas DSG3 is expressed throughout the epidermis (Mahoney et al., 1999).Dermatitis Herpetiformis and Celiac Disease Increase the Risk of Bullous Pemphigoid
Bullous pemphigoid (BP) and dermatitis herpetiformis (DH) are autoimmune bullous skin diseases. DH has been described to evolve into BP and the two diseases can have overlapping clinical appearances and diagnostic findings, but the association between DH and BP has not previously been studied in a large population. To evaluate DH and celiac disease as risk factors for BP, we conducted a retrospective case-control study of patients with BP and matched controls with basal cell carcinoma diagnosed in Finland between 1997 and 2013.BP180 Autoantibodies Target Different Epitopes in Multiple Sclerosis or Alzheimer’s Disease than in Bullous Pemphigoid
Neurologic patients have an increased risk for bullous pemphigoid (BP), in which autoantibodies target BP180, a cutaneous basement membrane protein also expressed in the brain. Here we show that 53.6% of sera from patients with multiple sclerosis (MS) (n = 56) had IgG reactivity against full-length BP180 in immunoblotting, while in BP180 non-collagenous 16A ELISA (n = 143), only 7.7% of MS samples studied were positive. Epitope mapping with 13 fusion proteins covering the entire BP180 polypeptide revealed that in MS and Alzheimer’s disease (AD) patients, IgG autoantibodies target regions located in the intracellular and mid-extracellular parts of BP180, but not the well-known BP epitopes located in the non-collagenous 16A domain and the distal part of extracellular domain.Large International Validation of ABSIS and PDAI Pemphigus Severity Scores
The Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity-Score (ABSIS) scores have been proposed to provide an objective measure of pemphigus activity. These scores have been evaluated only on already treated patients mainly with mild to moderate activity. The objective was to assess the interrater reliability of ABSIS and PDAI scores and their correlation with other severity markers in a large international study. Consecutive patients with newly diagnosed pemphigus were enrolled in 31 centers.Incidence and Mortality of Pemphigus in France
The incidence of pemphigus varies from 0.5 to 34 cases/million inhabitants/year, with the highest incidence rates in Brazil (Hans-Filho et al., 1996; Ishii et al., 2008; Langan et al., 2008; Meyer and Misery, 2010). Additionally, although the prognosis of pemphigus patients is considered good in the literature, recent findings reported unusually high mortality rates (Almugairen et al., 2013; Langan et al., 2008).Modes of Action of Intravenous Immunoglobulin in Bullous Pemphigoid
Bullous pemphigoid is an autoantibody-mediated skin blistering disease. Previous studies revealed that intravenous Ig is therapeutic in animal models of bullous pemphigoid by saturating the IgG-protective receptor FcRn, thereby accelerating degradation of pathogenic IgG. Sasaoka et al. demonstrate that the inhibitory effects of intravenous Ig on bullous pemphigoid are also associated with negative modulation of cytokine production by keratinocytes.Identification of Immunodominant Th2-Cell Epitopes in Chinese Patients with Bullous Pemphigoid
Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease caused by autoantibodies targeting the juxtamembranous extracellular noncollagenous 16A (NC16A) domain of human collagen XVII (also known as BP180). Because T-helper (Th) cells are essential for antibody responses to antigens, we adopted an assay to map the immunodominant Th2-cell epitopes in NC16A. We synthesized 22 overlapping peptides spanning the entire sequence of BP180-NC16A and investigated the reactivity of Th2 cells from patients with BP to these peptides using the Enzyme-Linked ImmunoSpot (ELISPOT) assay.Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models
Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies to COL17. Currently, systemic corticosteroids are used as first-line treatments for BP; alternatively, intravenous administration of high-dose IgG (IVIG) has been shown to be effective for patients with steroid-resistant BP in clinical practice. However, the effect of IVIG on BP has not fully been investigated. To examine the effects and mechanisms of action of IVIG against BP, we performed IVIG experiments using two experimental BP mouse models.The HLA-DQB1*03:01 Is Associated with Bullous Pemphigoid in the Han Chinese Population
Bullous pemphigoid (BP) is a potentially fatal subepidermal blistering autoimmune disease that characteristically affects elderly patients who present with large tense bullae on the entire skin and frequently on the extremities (Nousari et al., 1999; Sami et al., 2004). Subepidermal blisters with inflammation are the hallmark of BP histology. Direct immunofluorescence of perilesional skin shows linear deposits of the C3 and IgG. Two hemidesmosomal antigens have been identified, one protein of approximately 230 kDa associated with the intracellular plaque (BPAG1, also known as BP230) (Stanley et al., 1981), and the other protein of approximately 180 kDa associated with transmembrane glycoprotein (BPAG2, also known as BP180) (Diaz et al., 1990).Vildagliptin Significantly Increases the Risk of Bullous Pemphigoid: A Finnish Nationwide Registry Study
Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease (Schmidt and Zillikens, 2013). BP has become more common over the past two decades (Försti et al., 2014; Joly et al., 2012; Langan et al., 2008). However, the underlying causes of the increasing incidence of BP are poorly understood. Altogether, over 50 drugs have been reported to induce BP (Stavropoulos et al., 2014). The use of dipeptidyl peptidase-4 inhibitors (DPP-4i), a class of drug used for the treatment of diabetes, has recently been scrutinized as a risk factor for BP, both in case reports (see Supplementary Table S1 online) and in national pharmacovigilance database reports (Bene et al., 2016; García et al., 2016), but large population-based studies are lacking.Increasing the Complement of Therapeutic Options in Bullous Pemphigoid
Bullous pemphigoid is a potentially life-threatening autoantibody-mediated dermatosis characterized by blister formation. Experimental mouse models of bullous pemphigoid feature complement-induced inflammation and tissue damage. Kasprick et al. now provide preclinical data that utilize ex vivo human skin assays and support testing of complement inhibition as a therapeutic strategy in human bullous pemphigoid.Eosinophils Mediate Tissue Injury in the Autoimmune Skin Disease Bullous Pemphigoid
Eosinophils are typically associated with unique inflammatory settings, including allergic inflammation and helminth infections. However, new information suggests that eosinophils contribute more broadly to inflammatory responses and participate in local immune regulation and the tissue remodeling/repair events linked with a variety of diseases. Eosinophilic infiltration has long been a histologic hallmark of bullous pemphigoid (BP), a subepidermal autoimmune blistering disease characterized by autoantibodies directed against basement membrane protein BP180.HLA-DQB1*03:01 as a Biomarker for Genetic Susceptibility to Bullous Pemphigoid Induced by DPP-4 Inhibitors
Dipeptidyl peptidase-4 inhibitor (DPP-4i) has been widely used to treat type 2 diabetes. DPP-4 inactivates incretins by catalyzing the cleavage of those proteins to inactive forms (Drucker, 2007). DPP-4i works by inhibiting the action of this enzyme and improves glycemic control (Aschner and Kipnes, 2006). DPP-4i has been known as a safe drug; however, an increased risk of bullous pemphigoid (BP) during DPP-4i exposure has been reported in diabetic patients administered DPP-4i (Béné et al., 2016).
