Análise do polimorfismo da região 3’não traduzida (3’NT) do gene HLA-G de pacientes com esclerose múltipla e neuromielite óptica da região noroeste do estado de São Paulo
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Data
2016-02-22
Autores
Souza, Andreia da Silva [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A esclerose múltipla (EM) e as desordens do espectro de neuromielite óptica (NMOSD) são doenças inflamatórias autoimunes com predileção pelo sistema nervoso central, sendo que a EM ocorre mais frequentemente em populações caucasianas, enquanto a NMO é mais frequente em indivíduos não caucasianos. O gene HLA-G codifica uma molécula com um importante papel na tolerância imunológica. Essa molécula foi primeiramente descrita na interface materno-fetal, onde foi associada ao sucesso da gravidez. Além disso, a expressão da molécula de HLA-G tem sido relatada em condições patológicas como câncer, infecções virais e doenças autoimunes, incluindo EM. O nível de expressão de HLA-G depende principalmente de fatores que modulam sua expressão transcricional e pós-transcricionalmente, tais como a região 3’não traduzida (3’NT) do gene através da manutenção da estabilidade do mRNA e da interação com microRNAs específicos. Alguns haplótipos de 3’NT foram associados a maior expressão de HLA-G, o que seria benéfico em desordens autoimunes. O objetivo deste estudo foi analisar os sítios polimórficos da região 3’NT do gene HLA-G de pacientes com EM e NMOSD. A região 3’ NT do gene HLA-G de 105 pacientes com EM, 54 pacientes NMOSD e 108 controles, foi sequenciada através do método Sanger. Foram identificados 10 sítios de variações, incluindo 14pb indel +3001C/T,+3003T/C, +3010G/C,+3027C/A, +3035C/T, +3142C/G, +3187G/A, +3196C/G, +3227G/A. Não foi encontrada qualquer associação desses alelos à EM quando comparada a controles saudáveis ou a NMOSD. Porém, comparado a controles, o alelo +3187A apareceu em maior frequência no grupo NMOSD e consequentemente o alelo +3187G e UTR-1(DelCTGCCCGCG), único haplótipo que carrega esse alelo, foram sub-representados nesse grupo, particularmente no grupo de pacientes soropositivos para anticorpos anti-AQP4. Por outro lado, o grupo de pacientes NMOSD soronegativos para anti-AQP4 apresentou maior frequência de UTR-6 (DelCTGCCCACG) quando comparado a controles saudáveis. Considerando que: i) o alelo +3187A está associado a menor expressão de HLA-G e ii) o alelo +3187A e o genótipo +3187AA são mais frequentes no grupo NMOSD, principalmente nos pacientes anti-AQP4 positivos, a baixa expressão de HLA-G poderia estar contribuindo para a quebra da tolerância imunológica na patogenia de NMOSD.
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory diseases with predilection for the central nervous system, and the MS occurs most frequently in Caucasian populations, while NMOSD is more frequent in non-Caucasian individuals. A key feature of MS and NMOSD is the breakdown of immunological tolerance. Human leukocyte antigen G (HLA-G) gene encodes a nonclassical HLA class I molecule that plays a pivotal role in immune tolerance, inhibiting different cell subsets involved in innate and adaptive immunity and autoimmune responses. Constitutive expression of HLA-G has been primarily observed in placenta, and ectopic expression been observed in cancer, allografts and autoimmune disorders. As a corollary, HLA-G expression is expected to be advantageous in autoimmune disorders. The regulation of the HLA-G gene may depend on transcriptional and posttranscriptional regulatory elements, such as HLA-G 3’untranslated region (UTR) by maintaining mRNA stability and interaction with specific microRNAs. The aim of this study was to verify polymorphic sites at HLA-G 3’UTR in MS and NMOSD patients. HLA-G 3’UTR of Brazilian patients with MS (n=105), NMO (n=54) and in healthy individuals (n=108) was typed using Sanger method. Ten variation sites were observed, including the 14bp indel +3001C/T,+3003T/C, +3010G/C,+3027C/A, +3035C/T, +3142C/G, +3187G/A, +3196C/G, +3227G/A. HLA-G 3'UTR allele, genotype and haplotype frequencies showed no differences after comparison of MS with controls and MS with NMOSD were closely similar. Compared to controls; i) the +3187A allele was overrepresented and UTR-1(DelCTGCCCGCG) that contains +3187G was underrepresented in NMOSD patients; ii) +3187A and +3187AA were overrepresented, whereas UTR-1(DelCTGCCCGCG) was underrepresented in NMO AQP4+ patients, and iii) the UTR-6 (DelCTGCCCACG) was overrepresented in NMO AQP4- patients. HLA-G 3’UTR polymorphic sites are differentially associated with neuromyelitis optica and multiple sclerosis further corroborating that NMO and MS are distinct diseases. Considering that: i) the +3187A allele has been associated with decreased expression of HLA-G, ii) the +3187A allele and AA genotype were overrepresented in NMOSD patients, particularly in those exhibiting AQP4 antibodies (AQP4 group), a low HLA-G expression may contribute to breakdown of immune tolerance in the pathogenesis of NMOSD.
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory diseases with predilection for the central nervous system, and the MS occurs most frequently in Caucasian populations, while NMOSD is more frequent in non-Caucasian individuals. A key feature of MS and NMOSD is the breakdown of immunological tolerance. Human leukocyte antigen G (HLA-G) gene encodes a nonclassical HLA class I molecule that plays a pivotal role in immune tolerance, inhibiting different cell subsets involved in innate and adaptive immunity and autoimmune responses. Constitutive expression of HLA-G has been primarily observed in placenta, and ectopic expression been observed in cancer, allografts and autoimmune disorders. As a corollary, HLA-G expression is expected to be advantageous in autoimmune disorders. The regulation of the HLA-G gene may depend on transcriptional and posttranscriptional regulatory elements, such as HLA-G 3’untranslated region (UTR) by maintaining mRNA stability and interaction with specific microRNAs. The aim of this study was to verify polymorphic sites at HLA-G 3’UTR in MS and NMOSD patients. HLA-G 3’UTR of Brazilian patients with MS (n=105), NMO (n=54) and in healthy individuals (n=108) was typed using Sanger method. Ten variation sites were observed, including the 14bp indel +3001C/T,+3003T/C, +3010G/C,+3027C/A, +3035C/T, +3142C/G, +3187G/A, +3196C/G, +3227G/A. HLA-G 3'UTR allele, genotype and haplotype frequencies showed no differences after comparison of MS with controls and MS with NMOSD were closely similar. Compared to controls; i) the +3187A allele was overrepresented and UTR-1(DelCTGCCCGCG) that contains +3187G was underrepresented in NMOSD patients; ii) +3187A and +3187AA were overrepresented, whereas UTR-1(DelCTGCCCGCG) was underrepresented in NMO AQP4+ patients, and iii) the UTR-6 (DelCTGCCCACG) was overrepresented in NMO AQP4- patients. HLA-G 3’UTR polymorphic sites are differentially associated with neuromyelitis optica and multiple sclerosis further corroborating that NMO and MS are distinct diseases. Considering that: i) the +3187A allele has been associated with decreased expression of HLA-G, ii) the +3187A allele and AA genotype were overrepresented in NMOSD patients, particularly in those exhibiting AQP4 antibodies (AQP4 group), a low HLA-G expression may contribute to breakdown of immune tolerance in the pathogenesis of NMOSD.
Descrição
Palavras-chave
HLA-G, 3’NT, UTR-1, +3187A, Esclerose múltipla, Neuromielite óptica, Multiple sclerosis, Neuromyelitis optica