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
Pemphigus foliaceus (PF) is an autoimmune blistering disease of the skin, clinically characterized by erosions and, histopathologically, by acantholysis. PF is endemic in the Brazilian Central-Western region. Numerous single nucleotide polymorphisms (SNPs) have been shown to affect the susceptibility for PF, including SNPs at long non-coding RNA (lncRNA) genes, which are known to participate in many physiological and pathogenic processes, such as autoimmunity. Here, we investigated whether the genetic variation of immune-related lncRNA genes affects the risk for endemic and sporadic forms of PF. We analysed 692 novel SNPs for PF from 135 immune-related lncRNA genes in 227 endemic PF patients and 194 controls. The SNPs were genotyped by Illumina microarray and analysed by applying logistic regression at additive model, with correction for sex and population structure. Six associated SNPs were also evaluated in an independent German cohort of 76 sporadic PF patients and 150 controls. Further, we measured the expression levels of two associated lncRNA genes (LINC-PINT and LY86-AS1) by quantitative PCR, stratified by genotypes, in peripheral blood mononuclear cells of healthy subjects. We found 27 SNPs in 11 lncRNA genes associated with endemic PF (p < .05 without overlapping with protein-coding genes). Among them, the LINC-PINT SNP rs10228040*A (OR = 1.47, p = .012) was also associated with increased susceptibility for sporadic PF (OR = 2.28, p = .002). Moreover, the A+ carriers of LY86-AS1*rs12192707 mark lowest LY86-AS1 RNA levels, which might be associated with a decreasing autoimmune response. Our results suggest a critical role of lncRNA variants in immunopathogenesis of both PF endemic and sporadic forms.
Assuntos
Antígenos de Superfície/genética , Pênfigo/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Antígenos de Superfície/imunologia , Predisposição Genética para Doença , Humanos , Pênfigo/imunologia , Polimorfismo de Nucleotídeo Único/imunologia , RNA Longo não Codificante/imunologiaRESUMO
Pemphigus foliaceus (PF) is an autoimmune blistering skin disease characterized by the presence of pathogenic autoantibodies against desmoglein 1, a component of intercellular desmosome junctions. PF occurs sporadically across the globe and is endemic in some Brazilian regions. Because PF is a B-cell-mediated disease, we aimed to study the impact of variants within genes encoding molecules involved in the different steps of B-cell development and antibody production on the susceptibility of endemic PF. We analysed 3,336 single nucleotide polymorphisms (SNPs) from 167 candidate genes genotyped with Illumina microarray in a cohort of 227 PF patients and 193 controls. After quality control and exclusion of non-informative and redundant SNPs, 607 variants in 149 genes remained in the logistic regression analysis, in which sex and ancestry were included as covariates. Our results revealed 10 SNPs within or nearby 11 genes that were associated with susceptibility to endemic PF (OR >1.56; p < 0.005): rs6657275*G (TGFB2); rs1818545*A (RAG1/RAG2/IFTAP);rs10781530*A (PAXX), rs10870140*G and rs10781522*A (TRAF2); rs535068*A (TNFRSF1B); rs324011*A (STAT6);rs6432018*C (YWHAQ); rs17149161*C (YWHAG); and rs2070729*C (IRF1). Interestingly, these SNPs have been previously associated with differential gene expression, mostly in peripheral blood, in publicly available databases. For the first time, we show that polymorphisms in genes involved in B-cell development and antibody production confer differential susceptibility to endemic PF, and therefore are candidates for possible functional studies to understand immunoglobulin gene rearrangement and its impact on diseases.
Assuntos
Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Pênfigo/genética , Pênfigo/imunologia , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/genética , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Brasil , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Expressão Gênica/genética , Expressão Gênica/imunologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/imunologia , Adulto JovemRESUMO
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/imunologiaAssuntos
Metilação de DNA/imunologia , Epigênese Genética/imunologia , Pênfigo/genética , Adulto , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Haplótipos/imunologia , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1/genética , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Masculino , Pênfigo/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by mucocutaneous lesions associated with benign and malignant neoplasms. Diagnostic criteria include the presence of chronic mucositis and polymorphic cutaneous lesions with occult or confirmed neoplasia; histopathological analysis exhibiting intraepidermal acantholysis, necrotic keratinocytes, and vacuolar interface dermatitis; direct immunofluorescence with intercellular deposits (IgG and C3) and at the basement membrane zone (IgG); indirect immunofluorescence with intercellular deposition of IgG (substrates: monkey esophagus and simple, columnar, and transitional epithelium); and, autoreactivity to desmogleins 1 and 3, desmocollins 1, 2, and 3, desmoplakins I and II, envoplakin, periplakin, epiplakin, plectin, BP230, and α-2-macroglobulin-like protein 1. Neoplasias frequently related to paraneoplastic pemphigus include chronic lymphocytic leukemia, non-Hodgkin lymphoma, carcinomas, Castleman disease, thymoma, and others. Currently, there is no standardized treatment for paraneoplastic pemphigus. Systemic corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, rituximab, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin have been used, with variable outcomes. Reported survival rates in 1, 2, and 5 years are 49%, 41%, and 38%, respectively.
Assuntos
Síndromes Paraneoplásicas/patologia , Síndromes Paraneoplásicas/terapia , Pênfigo/patologia , Pênfigo/terapia , Autoanticorpos/imunologia , Eritema/diagnóstico , Eritema/patologia , Humanos , Doenças da Boca/diagnóstico , Doenças da Boca/patologia , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/imunologia , Pênfigo/diagnóstico , Pênfigo/imunologia , Pele/patologiaRESUMO
BACKGROUND: El Bagre endemic pemphigus foliaceus (El Bagre-EPF) is a new variant of endemic pemphigus foliaceus present in the El Bagre area of Colombia, South America. Here, we investigate the presence of complement/C5-b9 in lesional skin of patients and matched controls from the endemic area. We also aim to compare the patient's autoantibody levels using indirect immunofluorescent titers (IIF) and correlate with the lesional presence of complement/C5b-9. METHODS: A case-control study was carried out by testing for the presence of complement/C5b-9 in lesional skin in 43 patients affected by El Bagre-EPF, as well as 43 matched, healthy controls from the endemic area. Skin biopsies were obtained and evaluated via hematoxylin and eosin staining, and immunohistochemistry. RESULTS: The presence of complement/C5b-9 was observed in all cases of the patients affected by El Bagre-EPF and was not observed in the controls from the endemic area (P < 0.001). The patients' autoantibody titers utilizing IIF for IgG and IgM showed correlation between higher autoantibody titers and stronger intensity of staining with complement/C5-b9 staining (P < 0.001). CONCLUSION: Patients affected by El Bagre-EPF have lesional deposition of complement/C5b, which correlates with disease severity and previously established serologies.
Assuntos
Proteínas do Sistema Complemento/imunologia , Pênfigo/imunologia , Pênfigo/patologia , Autoanticorpos/imunologia , Biópsia , Estudos de Casos e Controles , Colômbia/epidemiologia , Feminino , Humanos , Imuno-Histoquímica/instrumentação , Masculino , Pênfigo/epidemiologia , Índice de Gravidade de Doença , Pele/patologia , Dermatopatias/epidemiologia , Dermatopatias/imunologia , Dermatopatias/patologiaRESUMO
Abstract: Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by mucocutaneous lesions associated with benign and malignant neoplasms. Diagnostic criteria include the presence of chronic mucositis and polymorphic cutaneous lesions with occult or confirmed neoplasia; histopathological analysis exhibiting intraepidermal acantholysis, necrotic keratinocytes, and vacuolar interface dermatitis; direct immunofluorescence with intercellular deposits (IgG and C3) and at the basement membrane zone (IgG); indirect immunofluorescence with intercellular deposition of IgG (substrates: monkey esophagus and simple, columnar, and transitional epithelium); and, autoreactivity to desmogleins 1 and 3, desmocollins 1, 2, and 3, desmoplakins I and II, envoplakin, periplakin, epiplakin, plectin, BP230, and α-2-macroglobulin-like protein 1. Neoplasias frequently related to paraneoplastic pemphigus include chronic lymphocytic leukemia, non-Hodgkin lymphoma, carcinomas, Castleman disease, thymoma, and others. Currently, there is no standardized treatment for paraneoplastic pemphigus. Systemic corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, rituximab, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin have been used, with variable outcomes. Reported survival rates in 1, 2, and 5 years are 49%, 41%, and 38%, respectively.
Assuntos
Humanos , Síndromes Paraneoplásicas/patologia , Síndromes Paraneoplásicas/terapia , Pênfigo/imunologia , Pênfigo/patologia , Pênfigo/terapia , Síndromes Paraneoplásicas/imunologia , Pele/patologia , Autoanticorpos/imunologia , Pênfigo/diagnóstico , Eritema/diagnóstico , Eritema/patologia , Doenças da Boca/diagnóstico , Doenças da Boca/patologiaRESUMO
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
BACKGROUND: We have previously reported that about 30% of patients affected by a new variant of endemic pemphigus foliaceus (EPF) in El Bagre, Colombia (termed El Bagre-EPF or pemphigus Abreu-Manu) have systemic compromise. In the current study, we focused on studying autoreactivity to the kidney and its pathological correlations. AIM: To investigate patients with El Bagre-EPF for renal compromise. METHODS: We performed a case-control study, enrolling 57 patients with El Bagre-EPF and 57 controls from the endemic area, matched by age, sex, race, work activity, demographics and comorbidities. We took skin and renal biopsies; performed direct and indirect immunofluorescence, immunohistochemistry (IHC), confocal microscopy, immunoblotting, direct and indirect immune electron microscopy; and tested kidney function in all living patients. We also used IHC to study seven kidney autopsy samples. RESULTS: Of the 57 patients, 19 had autoantibodies to kidney, with polyclonal reactivity (P < 0.01). Most cases were positive along the basement membrane of the proximal tubules, but in some cases there was also positivity against the glomeruli and/or mixed patterns. Fifteen patients had increases in serum urea and creatinine compared with controls (P < 0.01). The autoantibodies colocalized with commercial antibodies to desmoplakins I and II, p0071, armadillo repeat gene deleted in velo-cardio-facial syndrome (ARCVF) and myocardium-enriched zonula occludens-1-associated protein (MYZAP) (P < 0.01). All of the kidney disease autopsies showed alterations, mostly in the vessels. CONCLUSION: We demonstrate for the first time that one-third of patients with El Bagre-EPF have polyclonal autoantibodies to kidney. The kidneys showed a mixed histological pattern resembling lupus nephritis, with a diffuse proliferative Class IV (G) global diffuse pattern in active lesions, and additional interposition of membranoproliferative glomerulonephritis.