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Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2022.tde-16112022-154816
Document
Author
Full name
Ederson Valei Lopes de Oliveira
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2022
Supervisor
Committee
Roselino, Ana Maria Ferreira (President)
Abbade, Luciana Patricia Fernandes
Carvalho, Luciana Martins de
Donadi, Eduardo Antonio
Title in Portuguese
Polimorfismos genéticos dos receptores da Fcγ IgG nos pênfigos e no desfecho da resposta terapêutica ao Rituximabe
Keywords in Portuguese
FcγR
Pênfigo
Rituximabe
Single nucleotide polymorphism
Abstract in Portuguese
Introdução: Pênfigos são dermatoses autoimunes, cujas bolhas intraepidérmicas decorrem do evento acantólise, resultante da deposição de autoanticorpos IgG4 nas desmogleínas (DSGs). DSGs são proteínas (família das caderinas) responsáveis pela adesão entre os queratinócitos. Pênfigo vulgar (PV) acomete pele e mucosas devido à produção de antiDSG1 e antiDSG3; pênfigo foliáceo (PF) acomete exclusivamente a pele, por antiDSG1. Receptores da fração c gama da imunoglobulina G (FcγR IgG), que se encontram expressos nos leucócitos, são geneticamente determinados. Com as funções de ativar (FcγRIIa, FcγRIIIa, FcγRIIIb) ou inibir (FcγRIIb, FcγRIIIa) respostas imunológicas e a depender do polimorfismo (SNP) herdado, observar-se maior ou menor resposta frente a condições infecciosas e autoimunes (i.e, lúpus eritêmatoso e artrite reumatoide). Quanto ao tratamento dos pênfigos, além da corticoterapia associada ou não a imunossupressores, Rituximabe (RTX, anti-CD20) tem-se destacado como opção terapêutica, porém SNPs FcγR IgG podem interferir favorável ou desfavoravelmente na resposta observada. Hipótese: SNPs FcγR IgG podem associar-se com suscetibilidade e/ou proteção a PV e PF, e com a resposta ao Rituximabe. Objetivos: Determinar as distribuições dos SNPs FcγR IgG em pacientes com PV e PF, comparando-os a controles do sudeste brasileiro, região prevalente para pênfigos. Associar esses SNPs com o tempo de duração da completa remissão da doença (CR), nos PV e PF tratados com RTX. Casuística e métodos: Estudo analítico transversal, 225 pacientes: 117 PV (81 mulheres, 44,9±15,8 anos) e 108 PF (58 mulheres, 32,3±16,6 anos), comparados a 187 controles (106 mulheres; 49,0±20,4 anos); atendidos no HCFMRP/USP (janeiro, 2008 a dezembro, 2017). Dentre os 225 pacientes, 22 receberam RTX (14 PV, 9 mulheres, 39,21±14,67 anos; e 8 PF, 3 mulheres, 35 ±19,43 anos), entre 2009 a 2017. SNPs dos FcγRIIa (rs1801274), FcγRIIb (rs1050501), FcγRIIIa (rs396991) e FcγRIIIb (rs52820103) foram determinados por PCR (Polymerase Chain Reaction). Sequenciamento genético foi necessário para determinar o SNP FcγRIIb. Os parâmetros duração da CR <14,5 meses e duração da CR ≥14,5 meses foram estabelecidos para avaliar associações entre os SNPs e resposta ao RTX. Para análises das frequências alélicas e genotípicas, recorreu-se ao Teste de Fisher. Nível de significância: p <0,05. Software Statistical Package for Social Science [SPSS versão 22.0 (Inc.Chicago.IL)]. Resultados: SNP FcγRIIa associa-se com PV, mas não com gênero ou formas clínicas: a variante alélica R131 prevalece no PV ao comparar com PF e controles (p = 0,012 e p = 0,008, respectivamente); o genótipo RR131 prevalece no PV em relação aos controles (p = 0,030), configurando suscetibilidade. O genótipo HH131 associa-se com proteção ao PV quando comparado com PF e controles (p = 0,012 e p = 0,008, respectivamente). O SNP FcγRIIIa associa-se com PF, mas não com formas clínicas: genótipos VV158 e FF158 prevalecem no PF ao comparar com PV e controles (p = 0,0002 e p <0,0001; p <0,0001 e p <0,0001, respectivamente). Nos pacientes PF, genótipo VV e alelo V associam-se com o gênero feminino. SNPs FcγRIIb e FcγRIIIb: sem associações com PV e PF. A combinação haplotípica HR+IT+VF+*01/02 encontra-se mais frequente no PV e nos controles quando comparados com PF (p = 0,007 e p = 0,046, respectivamente). A ausência desta combinação sugere proteção ao PF. Dentre os 22 pacientes tratados com RTX, não há associações entre os SNPs FcγRIIa, IIb, IIIa e IIIb, seja naqueles com CR <14,5 meses, seja nos que alcançaram CR ≥14,5 meses. Conclusões: SNPs FcγR IgG associam-se com PV e PF no sudeste do Brasil. O alelo FcγRIIaR associa-se com suscetibilidade ao PV. Os genótipos FcγRIIIaVV e FcγRIIIaFF associam-se com suscetibilidade ao PF. O alelo FcγRIIIaV e o genótipo FcγRIIIaVV, no PF, associam-se com o gênero feminino. A ausência da combinação HR+IT+VF+*01/02 sugere proteção ao PF. Não se observa associações entre os SNPs FcγRIIb e IIIb com PV ou PF. Tempo prolongado de CR após uso do RTX não se associa com os SNPs avaliados.
Title in English
Influence of genetic polymorphisms of IgG Fcγ receptors in pemphigus and therapeutic response to Rituximab
Keywords in English
FcγR
Pemphigus
Rituximab
Single nucleotide polymorphism
Abstract in English
Introduction: Pemphigus is autoimmune dermatoses whose intraepidermal blisters result from the acantholysis phenomenon, stemming from the deposition of IgG4 autoantibodies in desmogleins (DSGs). Desmogleins, proteins of the cadherin family, are responsible for adhesion between keratinocytes. Pemphigus Vulgaris (PV) affects the skin and mucous membranes due to the production of antiDSG1 and antiDSG3; Pemphigus Foliaceus (PF) affects the skin exclusively due to anti-DSG1. The immunoglobulin G fraction c gamma receptors (FcγR IgG), expressed in leukocytes are genetically determined. With the functions of activating (FcγRIIa, FcγRIIIa, FcγRIIIb) or inhibiting (FcγRIIb, FcγRIIIa) immune responses according to the inherited singlenucleotide polymorphism (SNP) a greater or lesser response of the individual to infectious and autoimmune conditions (i.e., lupus erythematosus and rheumatoid arthritis). As for the treatment of pemphigus, in addition to corticosteroid therapy with or without immunosuppressants, Rituximab (RTX, anti-CD20) has been highlighted as a therapeutic option; however FcγR IgG SNPs interfere favorably or unfavorably in the observed response. Hypothesis: FcγR IgG SNPs may be associated with susceptibility and/or protection to PV and PF, and with the response to RTX. Objectives: To determine the distributions of FcγR IgG SNPs in patients with PV and PF compared to controls from southeastern Brazil, a prevalent pemphigus region; and to associate IgG FcγR SNPs and the time to complete disease remission (CDR) of PV and PF patients who received RTX as a therapeutic modality. Material and methods: Cross-sectional study, 225 patients: 117 PV (81 women, 44.9±15.8 years) and 108 PF (58 women, 32.3±16.6 years), compared to 187 controls (106 women; 49.0±20.4 years); attended at the HC-FMRP/USP (January, 2008 to December, 2017). Among the 225 patients, 22 received RTX (14 PV, 9 women, 39.21±14.67 years; and 8 PF, 3 women, 35 ±19.43 years), between 2009 and 2017. SNPs of FcγRIIa (rs1801274), FcγRIIb (rs1050501), FcγRIIIa (rs396991) and FcγRIIIb (rs52820103) were determined by PCR (Polymerase Chain Reaction). Genetic sequencing was necessary to determine the FcγRIIb SNP. The parameters CR duration <14.5 months and CR duration ≥14.5 months were established to assess associations between SNPs and response to RTX. For the analysis of allelic and genotypic frequencies, Fisher's test was used. The significance level was set at p<0.05.Software Statistical Package for Social Science [SPSS version 22.0 (Inc.Chicago.IL)]. Results: FcγRIIa SNP is associated with PV, but not with gender or clinical forms: the allelic variant R131 prevails in PV when compared with PF and controls (p = 0.012 and p = 0.008, respectively); the RR131 genotype prevails in the PV in relation to controls (p = 0.030), configuring susceptibility. The HH131 genotype is associated with protection from PV when compared to PF and controls (p = 0.012 and p = 0.008, respectively). The FcγRIIIa SNP is associated with PF, but not with clinical forms: genotypes VV158 and FF158 prevail in PF when compared to PV and controls (p = 0.0002 and p <0.0001; p <0.0001 and p <0.0001, respectively). In PF patients, VV genotype and V allele are associated with the female gender. FcγRIIb and FcγRIIIb SNPs: no associations with PV and PF. The haplotypic combination HR+IT+VF+*01/02 is more frequent in PV and controls when compared with PF (p = 0.007 and p = 0.046, respectively). The absence of this combination suggests protection to PF. Among the 22 patients treated with RTX, there are no associations between the SNPs FcγRIIa, IIb, IIIa and IIIb, either in those with CR <14.5 months or in those who reached CR ≥14.5 months.
 
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Publishing Date
2022-11-24
 
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