The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem)

We report here a relationship between intramolecular epitope spreading and the clinical onset of the endemic form of pemphigus foliaceus in a Brazilian community with a high prevalence and incidence of the disease. Also known as Fogo Selvagem (FS), this disease is characterized by severe skin blistering and pathogenic anti–desmoglein-1 (Dsg1) autoantibodies. These autoantibodies bind the Dsg1 ectodomain and trigger keratinocyte cell detachment, the hallmark of FS. We show that (a) sera from FS patients in the preclinical stage recognized epitopes on the COOH-terminal EC5 domain of Dsg1, (b) disease onset was associated with the emergence of antibodies specific for epitopes on the NH2-terminal EC1 and EC2 domains, (c) all sera from FS patients with active disease recognized the EC1 and/or EC2 domains, and (d) sera from FS patients in remission showed reactivity restricted to EC5. These results suggest that anti-Dsg1 autoantibodies in FS are initially raised against the COOH-terminal EC5 domain of Dsg1 in individuals without skin disease; in genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading toward epitopes on the NH2-terminal EC1 and EC2 domains of Dsg1 leading to disease onset. Moreover, intramolecular epitope spreading may also modulate remissions and relapses of FS

Prevalence of Anti-Desmoglein-3 Antibodies in Endemic Regions of Fogo Selvagem in Brazil

Fogo selvagem (FS), the endemic form of pemphigus foliaceus (PF), is an autoimmune blistering disease characterized by autoantibodies against desmoglein 1. The Terena reservation of Limao Verde in Mato Grosso do Sul, Brazil, is a previously identified focus of disease. Autoantibodies against desmoglein 3 (Dsg3) have also been detected in sera from patients with FS. In an effort to further characterize the serological, geographical, and clinical epidemiology of the disease, we sought to determine the prevalence of anti-Dsg3 autoantibodies in sera from normal subjects living outside of and in an endemic area using an ELISA. Anti-Dsg3 antibodies were detected in 53 of 146 normal subjects from Limao Verde (36%), and in eight of 140 normal subjects from surrounding areas (6%). A significant trend was observed in the proportion of positive tests relative to distance from the endemic area (

The IgM Anti-Desmoglein 1 Response Distinguishes Brazilian Pemphigus Foliaceus (Fogo Selvagem) from Other Forms of Pemphigus

Fogo selvagem (FS) and pemphigus foliaceus (PF) possess pathogenic IgG anti-desmoglein 1-(Dsg1) autoantibodies. Although PF occurs sporadically, FS is endemic in Limao Verde (LV), Brazil (3.4% prevalence). IgM anti-Dsg1 were detected in 58% FS LV patients (n=31), 19% of FS patients from Hospital-Campo Grande (n=57), 19% from Hospital-Goiania (n=42), 12% from Hospital-Sao Paulo (n=56), 10% of PF patients from United States (n=20), and 0% of PF patients from Japan (n=20). Pemphigus vulgaris (n=40, USA and Japan), bullous pemphigoid (n=40, USA), and healthy donors (n=55, USA) showed negligible percentages of positive sera. High percentages of positive IgM anti-Dsg1 were found in healthy donors from four rural Amerindian populations (42% of 243) as compared with urban donors (14% of 81; P<0.001). More than 50% of healthy donors from LV (n = 99, age 5-20 years) possess IgM anti-Dsg1 across ages, whereas IgG-anti-Dsg1 was detected in 2.9% (age 5-10 years), 7.3% (age 11-15 years), and 29% of donors above age 16. IgM anti-Dsg1 epitopes are Ca2+and carbohydrate-independent. We propose that IgM anti-Dsg1 are common in FS patients in their native environment and uncommon in other pemphigus phenotypes and in FS patients who migrate to urban hospitals. Recurrent environmental antigenic exposure may lead to IgM and IgG responses that trigger FS

Basal cell carcinoma - epidemiology, pathogenesis, pathology, and association with inflammation biomarkers. A review

Basal cell carcinoma is the most common malignant neoplasm in humans, with low mortality, high morbidity, and exposure to solar radiation (UVB and UVA) is the most critical risk factor. Ultraviolet B rays generate mutagenic photoproducts in DNA and mutations in important genes regulating cellular functions, such as the tumor suppressor gene TP53. Ultraviolet A rays generate cytotoxic and mutagenic free radicals, potentiating the effects of UVB rays.. There is current evidence to support the role of inflammatory biomarkers related to tumorigenesis of basal cell carcinoma

IgG Autoantibody Response against Keratinocyte Cadherins in Endemic Pemphigus Foliaceus (Fogo Selvagem)

It is well established that autoantibodies against desmoglein 3 and desmoglein 1 (Dsg1) are relevant in the pathogenesis of pemphigus vulgaris and pemphigus foliaceus, including its endemic form fogo selvagem (FS). Isolated reports have shown that in certain patients with these diseases, autoantibodies against other desmosomal cadherins and E-cadherin may also be present. The goal of this investigation was to determine whether FS patients and normal individuals living in endemic areas possess autoantibodies against other desmosomal cadherins and E-cadherin. By testing a large number of FS and endemic control sera by ELISA, we found a consistent and specific autoantibody response against Dsg1 and other keratinocyte cadherins in these individuals, which is quite different from healthy individuals from the United States (US controls). Overall, the highest correlations among the autoantibody responses tested were in the endemic controls, followed by FS patients, and lowest in the US controls. These findings suggest that multiple, perhaps cross-reactive, keratinocyte cadherins are recognized by FS patients and endemic controls.NIH [R01-AR30281, R01-AR32599, T32-AR07369

Development of an IgG4-based Classifier/Predictor of Endemic Pemphigus Foliaceus (Fogo Selvagem)

Fogo Selvagem (FS) is mediated by pathogenic, predominantly IgG4, anti-Dsg1 autoantibodies and is endemic in Limao Verde (LV), Brazil. IgG and IgG-subclass autoantibodies were tested in a sample of 214 FS patients and 261 healthy controls by Dsg1-ELISA. For model selection, the sample was randomly divided into training (50%), validation (25%) and test (25%) sets. Using the training and validation sets, IgG4 was chosen as the best predictor of FS, with index values above 6.43 classified as FS. Using the test set, IgG4 has sensitivity 92% (95% CI: 82−95%), specificity 97% (95% CI: 89−100%) and area under the curve 0.97 (95% CI: 0.94−1.00). The IgG4 positive predictive value (PPV) in LV (3% FS prevalence) was 49%. The sensitivity, specificity and PPV of IgG anti-Dsg1 were 87%, 91% and 23%, respectively. The IgG4-based classifier was validated by testing 11 FS patients before and after clinical disease and 60 Japanese pemphigus patients. It classified 21/96 normal individuals from a LV cohort as having FS serology. Based on its PPV, half of the 21 individuals may currently have preclinical FS and could develop clinical disease in the future. Identifying individuals during preclinical FS will enhance our ability to identify etiological agent(s) triggering FS

An Insight into the Sialotranscriptome of Triatoma matogrossensis, a Kissing Bug Associated with Fogo Selvagem in South America

Triatoma matogrossensis is a Hemiptera that belongs to the oliveirai complex, a vector of Chagas' disease that feeds on vertebrate blood in all life stages. Hematophagous insects' salivary glands (SGs) produce potent pharmacologic compounds that counteract host hemostasis, including anticlotting, antiplatelet, and vasodilatory molecules. Exposure to T. matogrossensis was also found to be a risk factor associated with the endemic form of the autoimmune skin disease pemphigus foliaceus, which is described in the same regions where Chagas' disease is observed in Brazil. To obtain a further insight into the salivary biochemical and pharmacologic diversity of this kissing bug and to identify possible allergens that might be associated with this autoimmune disease, a cDNA library from its SGs was randomly sequenced. We present the analysis of a set of 2,230 (SG) cDNA sequences, 1,182 of which coded for proteins of a putative secretory nature

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

Peer reviewe