RESUMEN
Fogo Selvagem (FS), the endemic form of pemphigus foliaceus, is mediated by pathogenic IgG4 autoantibodies against the amino-terminal extracellular cadherin domain of the desmosomal cadherin desmoglein 1 (Dsg1). Here we define the detailed epitopes of these pathogenic antibodies. Proteolytic footprinting showed that IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide (A129LNSMGQDLERPLELR144) from the EC1 domain of Dsg1 that overlaps the binding site for an adhesive-partner desmosomal cadherin molecule. Mutation of Dsg1 residues M133 and Q135 reduced the binding of FS IgG4 autoantibodies to Dsg1 by â¼50%. Molecular modeling identified two nearby EC1 domain residues (Q82 and V83) likely to contribute to the epitope. Mutation of these residues completely abolished the binding of FS IgG4 to Dsg1. Bead aggregation assays showed that native binding interactions between Dsg1 and desmocollin 1 (Dsc1), which underlie desmosome structure, were abolished by Fab fragments of FS IgG4. These results further define the molecular mechanism by which FS IgG4 autoantibodies interfere with desmosome structure and lead to cell-cell detachment, the hallmark of this disease.
Asunto(s)
Autoanticuerpos/metabolismo , Desmogleína 1/inmunología , Desmosomas/metabolismo , Epítopos de Linfocito B/inmunología , Inmunoglobulina G/metabolismo , Pénfigo/inmunología , Péptidos/inmunología , Animales , Autoanticuerpos/inmunología , Brasil/epidemiología , Células Cultivadas , Enfermedades Endémicas , Mapeo Epitopo , Humanos , Inmunización Pasiva , Inmunoglobulina G/inmunología , Ratones , Ratones Endogámicos BALB C , Mutagénesis Sitio-Dirigida , Pénfigo/epidemiología , Unión Proteica , Conformación ProteicaRESUMEN
The environmental factors that contribute to the development of autoimmune diseases are largely unknown. Endemic pemphigus foliaceus in humans, known as Fogo Selvagem (FS) in Brazil, is mediated by pathogenic IgG4 autoantibodies against desmoglein 1 (Dsg1). Clusters of FS overlap with those of leishmaniasis, a disease transmitted by sand fly (Lutzomyia longipalpis) bites. In this study, we show that salivary Ags from the sand fly, and specifically the LJM11 salivary protein, are recognized by FS Abs. Anti-Dsg1 monoclonal autoantibodies derived from FS patients also cross-react with LJM11. Mice immunized with LJM11 generate anti-Dsg1 Abs. Thus, insect bites may deliver salivary Ags that initiate a cross-reactive IgG4 Ab response in genetically susceptible individuals and lead to subsequent FS. Our findings establish a clear relationship between an environmental, noninfectious Ag and the development of potentially pathogenic autoantibodies in an autoimmune disease.
Asunto(s)
Autoanticuerpos/inmunología , Reacciones Cruzadas , Mordeduras y Picaduras de Insectos/complicaciones , Pénfigo/inmunología , Psychodidae/inmunología , Animales , Especificidad de Anticuerpos , Autoantígenos/inmunología , Brasil , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoprecipitación , Mordeduras y Picaduras de Insectos/epidemiología , Mordeduras y Picaduras de Insectos/inmunología , Ratones , Glándulas Salivales/inmunologíaRESUMEN
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.