RESUMO
Sand flies are hematophagous insects responsible for the transmission of vector-borne diseases to humans. Prominent among these diseases is Leishmaniasis that affects the skin and mucous surfaces and organs such as liver and spleen. Importantly, the function of blood-sucking arthropods goes beyond merely transporting pathogens. The saliva of vectors of disease contains pharmacologically active components that facilitate blood feeding and often pathogen establishment. Transcriptomic and proteomic studies have enumerated the repertoire of sand fly salivary proteins and their potential use for the control of Leishmaniasis, either as biomarkers of vector exposure or as anti-Leishmania vaccines. However, a group of specific sand fly salivary proteins triggers formation of cross-reactive antibodies that bind the ectodomain of human desmoglein 1, a member of the epidermal desmosomal cadherins. These cross-reactive antibodies are associated with skin autoimmune blistering diseases, such as pemphigus, in certain immunogenetically predisposed individuals. In this review, we focus on two different aspects of sand fly salivary proteins in the context of human disease: The good, which refers to salivary proteins functioning as biomarkers of exposure or as anti-Leishmania vaccines, and the bad, which refers to salivary proteins as environmental triggers of autoimmune skin diseases.
Assuntos
Leishmaniose , Psychodidae , Animais , Autoimunidade , Leishmaniose/prevenção & controle , Proteômica , Proteínas e Peptídeos SalivaresRESUMO
Fogo selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P < 0.001 for both). The levels of IgG anti-DSG1 and IgG4 anti-LJM17 and anti-LJM11 antibodies correlated positively in normal settlers and patients with FS. Mice immunized with recombinant LJM17 produced IgG1 antibodies (human IgG4 homolog) that strongly cross-reacted with recombinant DSG1; these IgG1 antibodies were inhibited by LJM17, LJM11, and DSG1 in a dose-dependent manner. However, they did not bind human or mouse epidermis by indirect immunofluorescence. Lastly, we identified short-sequence homologies of surface-exposed residues within the human DSG1 ectodomain and LJM17. Inoculation by LJM17 from L. longipalpis-elicited DSG1-cross-reactive IgG4 antibodies may lead to FS in genetically predisposed individuals.
Assuntos
Mordeduras e Picadas/imunologia , Desmogleína 1/imunologia , Proteínas de Insetos/imunologia , Pênfigo/imunologia , Psychodidae/imunologia , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Mordeduras e Picadas/epidemiologia , Mordeduras e Picadas/patologia , Brasil/epidemiologia , Reações Cruzadas , Modelos Animais de Doenças , Doenças Endêmicas , Epiderme/imunologia , Epiderme/patologia , Humanos , Insetos Vetores/imunologia , Insetos Vetores/parasitologia , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Camundongos , Pênfigo/epidemiologia , Pênfigo/patologia , Psychodidae/parasitologia , Proteínas Recombinantes/imunologia , Proteínas e Peptídeos Salivares/imunologiaRESUMO
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.
Assuntos
Autoanticorpos/metabolismo , Desmogleína 1/imunologia , Desmossomos/metabolismo , Epitopos de Linfócito B/imunologia , Imunoglobulina G/metabolismo , Pênfigo/imunologia , Peptídeos/imunologia , Animais , Autoanticorpos/imunologia , Brasil/epidemiologia , Células Cultivadas , Doenças Endêmicas , Mapeamento de Epitopos , Humanos , Imunização Passiva , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mutagênese Sítio-Dirigida , Pênfigo/epidemiologia , Ligação Proteica , Conformação ProteicaRESUMO
OBJECTIVES: Fogo Selvagem (FS) in Limao Verde (LV), Brazil shows clinical and histological features of pemphigus foliaceus (PF) and shares pathogenic IgG4 anti-desmoglein 1 (Dsg1) autoantibodies. Previously, our group reported that mothers with active FS deliver babies with normal skin and low/negative titers of IgG4 autoantibodies by indirect immunofluorescence. It was postulated that maternal pathogenic IgG4 autoantibodies do not cross the placenta due to differential receptor mediated transplacental passage of IgG subclasses. It was also thought that placental Dsg1 may immunoadsorb pathogenic autoantibodies from the mother; hence pathogenic IgG4 autoantibodies do not reach the baby. In this study we use a Dsg1-specific ELISA to test anti-Dsg1 autoantibodies of the IgM, IgG and the IgG subclasses in the sera of 68 pairs of normal mothers and their neonates living in a highly endemic area of FS. Determination of these baseline anti-Dsg1 autoantibodies will allow us to follow and predict in this and other cohorts the appearance of preclinical serological markers of FS. METHODS: The sera of mothers and neonates living in the endemic region were tested by ELISA for IgM, IgG and IgG subclasses using recombinant Dsg1 and anti-IgG subclass-specific monoclonal antibodies. RESULTS: The index values of anti-Dsg1 IgG1, IgG2 and IgG3 are similar in mothers and neonates (all p>0.18), while the index values of IgM, total IgG and IgG4 are higher in mothers (all p<0.001). CONCLUSIONS: Narrowing the IgM, IgG and IgG subclasses of mothers and neonates to autoantibodies against Dsg1, we found, as expected, that IgM remains only in maternal circulation. In three mothers and two neonates we detected IgG4 anti-Dsg1 autoantibodies above the normal range. The remaining IgG subclasses show low values. The results of the neonatal sera will serve as a baseline for ongoing seroepidemiological studies of children and adults in the endemic regions of FS.
RESUMO
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.
Assuntos
Autoanticorpos/imunologia , Caderinas de Desmossomos/imunologia , Imunoglobulina G/imunologia , Queratinócitos/imunologia , Pênfigo/imunologia , Adulto , Brasil , Caderinas/genética , Caderinas/imunologia , Reações Cruzadas/imunologia , Desmogleína 1/genética , Desmogleína 1/imunologia , Desmogleína 2/genética , Desmogleína 2/imunologia , Desmogleína 3/genética , Desmogleína 3/imunologia , Desmogleínas/genética , Desmogleínas/imunologia , Caderinas de Desmossomos/genética , Humanos , Curva ROC , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Estados UnidosRESUMO
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.
Assuntos
Técnicas Imunoenzimáticas/métodos , Imunoglobulina G/química , Pênfigo/diagnóstico , Pênfigo/imunologia , Adolescente , Adulto , Brasil , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/metabolismo , Japão , Modelos Biológicos , Valor Preditivo dos TestesRESUMO
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.