RESUMO
BACKGROUND: Anti-desmoglein (Dsg)1 is produced in pemphigus foliaceus (PF), affecting exclusively the skin. Pemphigus vulgaris (PV) shows the production of anti-Dsg3 in the mucosal form, and anti-Dsg1 and 3 in the mucocutaneous form. Anti-Dsg3 autoantibodies have been rarely reported in PF. OBJECTIVES: To determine the factors associated with the production and pathogenicity of anti-Dsg3 in PF. METHODS: Comparative analytical study of three patients groups: 16 PF-anti-Dsg3+, and 42 PF-anti-Dsg3(-) and 22 PV treatment-naïve cases. Serum was used in the anti-Dsg1 and 3 ELISA, and in immunoblotting (IB) with human epidermis extract. The expression of Dsg1 and 3 in paraffin sections was analyzed by immunohistochemistry (IHC). HLA-DRB1 alleles were compiled from a database. RESULTS: In the PF-anti-Dsg3+ group: age range similar to that of the PV group (pâ¯>â¯0.9999); predominance of the generalized form of PF (pâ¯=â¯0.002); anti-Dsg3 titers lower than those of PV (pâ¯<â¯0.0001); IB confirmed Dsg3 identification in one (8.33%) of 12 patients; IHC showed exclusive cytoplasmic internalization of Dsg1; HLA-DRB1 alleles of susceptibility to PF, with the absence of alleles associated with PV, in the five typed patients. STUDY LIMITATIONS: Most of the patients in the PF-anti-Dsg3+ group were undergoing treatment. CONCLUSION: The presence of anti-Dsg3 antibodies in PF was related to older age (comparable to that of PV) and the generalized form of PF. The non-pathogenicity of anti-Dsg3 antibodies in PF can be attributed to the low serum anti-Dsg3 titers, the lack of Dsg3 internalization as detected by IHC, and the absence of PV-associated HLA-DRB1 alleles.
Assuntos
Autoanticorpos , Desmogleína 1 , Desmogleína 3 , Imuno-Histoquímica , Pênfigo , Humanos , Pênfigo/imunologia , Desmogleína 3/imunologia , Autoanticorpos/imunologia , Autoanticorpos/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Desmogleína 1/imunologia , Ensaio de Imunoadsorção Enzimática , Adulto Jovem , Immunoblotting , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Idoso de 80 Anos ou mais , AdolescenteRESUMO
BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are subtypes of pemphigus with distinct clinical and laboratory features. The transition between these two subtypes has rarely been reported previously. METHODS: The data of PV patients who exhibited clinical and immunoserological transition to PF during the follow-up period were retrospectively evaluated regarding their demographical, clinical, and laboratory characteristics. RESULTS: Among 453 patients diagnosed with PV, 13 (2.9%) patients exhibited clinical and immunoserological transition from PV to PF. The mean age of PV patients at the time of diagnosis was 39.8 ± 14.7 (19â62) years and 7 (53.8%) of them were female. These patients showed clinical and immunoserological transition from PV to PF after a period ranging from 4 months to 13 years (mean 36.2 ± 41 months). In addition to typical clinical features of PF, all patients had positive anti-desmoglein-1 and negative anti-desmoglein-3 antibody levels after the clinical transition had occurred without any mucosal involvement. During a mean 7.8 ± 5.8 (2â21) years of follow-up period after the transition from PV to PF, only one female patient had experienced a re-transition to PV characterized by a relapse of disease involving mucosal surfaces with positive anti-desmoglein-3 antibody levels following a 5-year period of remission period without treatment. STUDY LIMITATIONS: Single-center study with a retrospective study design. CONCLUSION: Our series is the largest group of patients reported to show the transition from PV to PF to date with a long follow-up period. The reason behind the disappearance of anti-desmoglein-3 antibodies and the pathogenesis of this phenomenon is not yet elucidated.
Assuntos
Pênfigo , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Pênfigo/patologia , Estudos Retrospectivos , Autoanticorpos , Desmogleína 1 , Desmogleína 3RESUMO
BACKGROUND: Anti-desmoglein 1 and 3 autoantibodies justify acantholysis in pemphigus; however, the pathogenesis of anti-desmoglein 2 is hypothetical. OBJECTIVE: To compare the participation of desmogleins 1, 2 and 3 through the production of serum autoantibodies, and protein and gene expression in the skin/mucosa of patients with pemphigus foliaceus and pemphigus vulgaris. METHODS: The autoantibodies were titrated by ELISA in 202 samples of pemphigus foliaceus, 131 pemphigus vulgaris, 50 and 57 relatives of patients with pemphigus foliaceus and pemphigus vulgaris, respectively, and 114 controls. Protein and gene expressions were determined by immunohistochemistry and qPCR in the skin/mucosa of 3 patients with pemphigus foliaceus and 3 patients with pemphigus vulgaris. RESULTS: Higher titers of anti-desmoglein 2 (optical density) resulted in pemphigus foliaceus and pemphigus vulgaris, when compared to controls (0.166; 0.180; 0.102; respectively; pâ¯<â¯0.0001). There was a correlation between anti-desmoglein 2 and anti-desmoglein 1 titers in pemphigus foliaceus (râ¯=â¯0.1680; pâ¯=â¯0.0206). There was no cross-reaction of anti-desmoglein 2 with desmoglein 1 and 3. Protein overexpression of desmoglein 2 was observed in intact and lesional skin of patients with pemphigus compared to the skin of controls. Internalization granules of desmoglein 1 and 3, but not of desmoglein 2, were observed in lesions of pemphigus foliaceus and pemphigus vulgaris, respectively. Gene overexpression of desmoglein 2 was observed in the mucosa. STUDY LIMITATIONS: Small sample size for the statistical analysis of protein and gene expression. CONCLUSION: Autoantibodies against desmoglein 2 are not pathogenic in pemphigus; protein and gene overexpression of desmoglein 2 in the skin and mucosa may be involved in acantholysis repair.
Assuntos
Pênfigo , Acantólise , Autoanticorpos , Desmogleína 1 , Desmogleína 2 , Desmogleína 3 , HumanosRESUMO
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
Resumen El pénfigo foliáceo es una enfermedadversículo ampollar autoinmune poco frecuente,caracterizada histopatológicamente por acantólisis, inducida por la presencia de autoanticuerpos frente a la desmogleína 1. El desprendimiento se localiza en los estratos más superficiales de la epidermis produciendo ampollas frágiles y erosiones. Se clasifica en endémico y no endémico o esporádico. Dentro de este último podemos encontrar una variedad localizada y una generalizada. Presentamos el caso de un paciente, con diagnósticoy confirmación histopatológica de pénfigo foliáceo y realizamos una breve revisión de la literatura.
Summary Foliaceus pemphigus is an infrequent autoimmune blistering verse disease characterized histopathologically by acantholysis, induced by the presence of autoantibodies against desmoglein 1. The detachment is located in the most superficial layers of the epidermis produces fragile blisters and erosions. It is classified as endemic, and not endemic or sporadic. Within the latter we can find a localized and a generalized variety. Presents the case of a patient, diagnosis and histopathological confirmation of a paper and makes a brief review of the literature.
Assuntos
Humanos , Masculino , Adulto , Pênfigo/diagnóstico , Pênfigo/tratamento farmacológico , Biópsia/métodos , Desmogleína 1/agonistasRESUMO
Pemphigus foliaceus (PF) is a blistering autoimmune skin disease rare in most of the world but endemic in certain regions of Brazil. PF is characterized by the detachment of epidermal cells and the presence of autoantibodies against desmoglein 1. In previous studies, we have shown that genetic polymorphisms and variable expression levels of certain leucocyte receptor complex (LRC) genes were associated with PF. However, the role of the LRC on PF susceptibility remained to be investigated. Here, we analysed 527 tag single nucleotide polymorphisms (SNPs) distributed within the 1·5â Mb LRC. After quality control, a total of 176 SNPs were analysed in 229 patients with PF and 194 controls. Three SNPs were associated with differential susceptibility to PF. The intergenic variant rs465169 [odds ratio (OR)â =â 1·50; Pâ =â 0·004] is located in a region that might regulate several immune-related genes, including VSTM1, LILRB1/2, LAIR1/2, LILRA3/4 and LENG8. The rs35336528 (ORâ =â 3·44; Pâ =â 0·009) and rs1865097 (ORâ =â 0·57; Pâ =â 0·005) SNPs in LENG8 and FCAR genes, respectively, were also associated with PF. Moreover, we found four haplotypes with SNPs within the KIR3DL2/3, LAIR2 and LILRB1 genes associated with PF (Pâ <â 0·05), which corroborate previously reported associations. Thus, our results confirm the importance of the LRC for differential susceptibility to PF and reveal new markers that might influence expression levels of several LRC genes, as well as candidates for further functional studies.
Assuntos
DNA Intergênico/genética , Genótipo , Leucócitos/fisiologia , Pênfigo/genética , Receptores Imunológicos/genética , Autoanticorpos/metabolismo , Brasil , Desmogleína 1/imunologia , Regulação da Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Análise Serial de TecidosRESUMO
BACKGROUND: Previous studies have shown oxidative stress in pemphigus vulgaris and pemphigus foliaceus, nevertheless, it remains unknown whether a similar response is characteristic of endemic pemphigus foliaceus in Peru. OBJECTIVES: To determine the oxidative stress response in endemic pemphigus foliaceus patients and subjects with positive for anti-desmoglein1 antibodies (anti-dsg1) from endemic areas of Peru. SUBJECTS AND METHODS: This is a cross-sectional study. The study population included 21 patients with Endemic Pemphigus foliaceus and 12 healthy subjects with anti-dsg1 antibodies from the Peruvian Amazon (Ucayali), as well as 30 healthy control subjects. Malondialdehyde, an indicator of lipid peroxidation by free radicals, was measured in serum. RESULTS: We collected 21 cases of endemic pemphigus foliaceus, 15 of them with active chronic disease and 6 in clinical remission. Serum malondialdehyde values in patients with chronic active evolution and healthy subjects with anti-dsg1 antibodies were statistically higher than those of healthy controls (p<0.001). There was no significant difference between serum values of localized and generalized clinical forms. STUDY LIMITATIONS: The main limitation of this present study is the small number of patients with endemic pemphigus and healthy subjects positive for desmoglein 1 antibodies. CONCLUSIONS: The increased serum levels of malondialdehyde in patients with chronic active endemic pemphigus foliaceus and healthy subjects from endemic areas with anti-dsg1 antibodies may suggest a contribution of systemic lipid peroxidation in the pathogenesis of endemic pemphigus foliaceus.
Assuntos
Anticorpos/sangue , Desmogleína 1/imunologia , Malondialdeído/sangue , Estresse Oxidativo/fisiologia , Pênfigo/imunologia , Pênfigo/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Estudos Transversais , Desmogleína 1/sangue , Doenças Endêmicas , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Peroxidação de Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Peru , Valores de Referência , Remissão Espontânea , Estatísticas não Paramétricas , Adulto JovemRESUMO
Abstract: Background: Previous studies have shown oxidative stress in pemphigus vulgaris and pemphigus foliaceus, nevertheless, it remains unknown whether a similar response is characteristic of endemic pemphigus foliaceus in Peru. Objectives: To determine the oxidative stress response in endemic pemphigus foliaceus patients and subjects with positive for anti-desmoglein1 antibodies (anti-dsg1) from endemic areas of Peru. Subjects and Methods: This is a cross-sectional study. The study population included 21 patients with Endemic Pemphigus foliaceus and 12 healthy subjects with anti-dsg1 antibodies from the Peruvian Amazon (Ucayali), as well as 30 healthy control subjects. Malondialdehyde, an indicator of lipid peroxidation by free radicals, was measured in serum. Results: We collected 21 cases of endemic pemphigus foliaceus, 15 of them with active chronic disease and 6 in clinical remission. Serum malondialdehyde values in patients with chronic active evolution and healthy subjects with anti-dsg1 antibodies were statistically higher than those of healthy controls (p<0.001). There was no significant difference between serum values of localized and generalized clinical forms. Study limitations: The main limitation of this present study is the small number of patients with endemic pemphigus and healthy subjects positive for desmoglein 1 antibodies. Conclusions: The increased serum levels of malondialdehyde in patients with chronic active endemic pemphigus foliaceus and healthy subjects from endemic areas with anti-dsg1 antibodies may suggest a contribution of systemic lipid peroxidation in the pathogenesis of endemic pemphigus foliaceus.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Adulto Jovem , Pênfigo/imunologia , Pênfigo/metabolismo , Estresse Oxidativo/fisiologia , Desmogleína 1/imunologia , Malondialdeído/sangue , Anticorpos/sangue , Peru , Valores de Referência , Remissão Espontânea , Ensaio de Imunoadsorção Enzimática , Peroxidação de Lipídeos/fisiologia , Estudos de Casos e Controles , Estudos Transversais , Estatísticas não Paramétricas , Doenças Endêmicas , Desmogleína 1/sangueRESUMO
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.