Caracterização clínica, molecular e imunológica de pacientes com síndrome poliglandular autoimune do tipo 1

• Autor(a) principal: Weiler, Fernanda Guimarães [UNIFESP]
• Data de Publicação: 2016
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3741792; https://repositorio.unifesp.br/handle/11600/46297
• topic: autoimmune polyendocrinopathies; chronic mucocutaneous candidiasis; hypoparathyroidism; adrenal insufficiency; autoimmunity; mutation; antibodies; autoimunidade; poliendocrinopatias autoimunes; candidíase mucocutânea crônica; hipoparatireoidismo; insuficiência adrenal; mutação; anticorpos

Introduction: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder defined by the association of at least two of the three major diseases: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and autoimmune adrenal insufficiency, however, many other autoimmune components may develop. In most cases, APS1 appears in infancy or childhood. The disease is caused by mutations in the AIRE gene, resulting in defective AIRE protein, which is essential for self-tolerance through thymic expression of peripheral self-proteins, and deletion of autoreactive T cells. In Brazil, however, the characteristics of APS1 patients are still unknown. Objective: To define the clinical profile of Brazilian APS1 patients; to perform mutational analysis of AIRE gene; to investigate genotype/phenotype correlations; to perform functional study of a novel mutation; and to measure specific autoantibodies. Patients and methods: Information about clinical history was evaluated by a questionnaire, and antibodies against interferon type I and interleukins 17A, 17F and 22 were measured in the sera of the patients. Genomic DNA was used to perform sequencing of all 14 exons and exon/intron boundaries of the AIRE gene. For localization analysis by immunofluorescence microscopy, HeLa cells were transfected with wild-type and mutant (c.560C>G) plasmids. Results: Thirteen patients with clinical diagnosis of APS1 were identified and in all cases the disease first appeared during infancy or childhood. Twenty different manifestations have been diagnosed. Besides being the first sign in the majority (77%), CMC was also the most frequent manifestation, present in all patients. Hypoparathyroidism was observed in 69% and adrenal insufficiency was diagnosed in 77%, while the complete triad was present in 54% of the sample. Every patient carried defects in AIRE, and among 10 identified mutations, 4 have never been reported (c.560C>G, c.966C>A, c.1096-2A>G and c.1347C>A). The most frequent mutation was the c.967_979del, which accounted for 36% of the alleles. As in other series, we were unable to identify correlations between phenotype and the detected mutations. Mutational analyses of relatives allowed the identification of APS1 in an asymptomatic child. In transiently transfected cells, the mutant c.560C>G protein was observed as abnormal perinuclear aggregates, which suggested the mutation harmful potential. All 10 confirmed APS1 patients that were tested for anti-interferon type I showed positive results, and we have found that anti-interleukin-17A titers were negatively correlated with number of manifestations in each patient. Thirteen patients suspected of having the syndrome were also investigated; one of them displayed another new mutation of AIRE, which is expected to be deleterious according to in silico simulations. Conclusions: We were able to identify 14 Brazilian patients with APS1, one of them still asymptomatic. In our cohort, CMC was the most prevalent disease, while the most common mutation was c.967_979del. We detected 4 novel mutations, and another mutation likely to be deleterious in a patient suspected of having the syndrome was also reported. Titers of anti-interleukin-17A were negatively correlated with number of manifestations. Screening for AIRE mutations and analysis of specific auto-antibodies are useful tools to establish the diagnosis in initial or atypical situations.