RESUMEN
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.
Asunto(s)
Autoanticuerpos/inmunología , Cadherinas Desmosómicas/inmunología , Inmunoglobulina G/inmunología , Queratinocitos/inmunología , Pénfigo/inmunología , Adulto , Brasil , Cadherinas/genética , Cadherinas/inmunología , Reacciones Cruzadas/inmunología , Desmogleína 1/genética , Desmogleína 1/inmunología , Desmogleína 2/genética , Desmogleína 2/inmunología , Desmogleína 3/genética , Desmogleína 3/inmunología , Desmogleínas/genética , Desmogleínas/inmunología , Cadherinas Desmosómicas/genética , Humanos , Curva ROC , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Estados UnidosRESUMEN
Fogo selvagem (FS) is mediated by pathogenic, predominantly IgG4, anti-desmoglein 1 (Dsg1) autoantibodies and is endemic in Limao Verde, 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 of 92% (95% confidence interval (95% CI): 82-95%), specificity of 97% (95% CI: 89-100%), and area under the curve of 0.97 (95% CI: 0.94-1.00). The IgG4 positive predictive value (PPV) in Limao Verde (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 foliaceus patients. It classified 21 of 96 normal individuals from a Limao Verde cohort as having FS serology. On the basis of 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 the etiological agent(s) triggering FS.
Asunto(s)
Técnicas para Inmunoenzimas/métodos , Inmunoglobulina G/química , Pénfigo/diagnóstico , Pénfigo/inmunología , Adolescente , Adulto , Brasil , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/metabolismo , Japón , Modelos Biológicos , Valor Predictivo de las PruebasRESUMEN
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. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub.
Asunto(s)
Autoanticuerpos/sangre , Desmogleína 1/inmunología , Enfermedades Endémicas/estadística & datos numéricos , Pénfigo/epidemiología , Pénfigo/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Calcio/metabolismo , Niño , Preescolar , Diagnóstico Diferencial , Epidermis/inmunología , Epítopos/inmunología , Femenino , Glicosilación , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad , Pénfigo/diagnóstico , Población Rural/estadística & datos numéricos , Estudios Seroepidemiológicos , Población Urbana/estadística & datos numéricosRESUMEN
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 (P < 0.001). Our seroepidemiological observations support the concept that the likely environmental trigger of the antibody response in FS is located in this endemic area, and that the population at risk to develop FS may also be at risk to develop an endemic form of pemphigus vulgaris as reported by our co-investigators from Brasilia.