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The implications of defective sialic acid conditions on cell immune response
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A miopatia GNE (GNEM) é uma doença congénita da glicosilação (CDG) resultante de mutações no GNE, o qual codifica uma enzima-chave na biossíntese do ácido siálico (SA). Baixos níveis de SA (hiposialilação) são característicos desta doença, porém, a sua relação com a fraqueza muscular progressiva observada continua pouco compreendida. Embora a GNEM não seja classificada como condição imune, biópsias musculares revelam alterações inflamatórias e imunológicas, incluindo a expressão do complexo maior de histocompatibilidade classe I (MHC-I), tipicamente associada a miopatias inflamatórias idiopáticas. Baixos níveis de SA estão também associados a uma maior expressão de MHC-I, sugerindo uma forte componente imunológica.
Atualmente, não existem terapias para a GNEM aprovadas pela Agência Europeia de Medicamentos (EMA) ou pela Food and Drug Administration (FDA).
Neste trabalho, explorou-se o papel do MHC-I como biomarcador de um possível me-canismo imune. Verificou-se que o HLA-A, um gene que codifica a cadeia pesada do MHC-I, é sobre-expresso em células deficientes em GNE. A TAP-binding protein like (TAPBPR), en-volvida na formação do complexo MHC-I/peptídeo, também se encontra sobre-expressa, sugerindo uma regulação positiva do mecanismo de apresentação antigénica via MHC-I. Para estudar a resposta imunológica em condições fisiologicamente mais relevantes, foram utilizados fibroblastos de doentes com GNEM, que apresentaram hiposialilação. Uma amostra de doente apresentou elevada expressão de MHC-I, indicando a ativação de vias imunológicas associadas à apresentação antigénica. O tratamento com um pró-fármaco promissor revelou tendência para aumentar a sialilação, não sendo, contudo, observada diminuição da expressão de MHC-I. Estes resultados realçam a necessidade de estudos envolvendo maior número de amostras de doentes e controlos, bem como uma análise glicómica mais detalhada. Este trabalho sublinha ainda a importância de investigar o envolvimento imunológico na GNEM, potencialmente ligado à deficiência de SA, como etapa essencial para compreender os mecanismos patológicos da doença e orientar o desenvolvimento de novas terapias.
GNE Myopathy (GNEM) is an ultra-rare congenital disorder of glycosylation (CDG) resulting from mutations in GNE, which encodes a key enzyme in sialic acid (SA) biosynthesis. Reduced levels of SA (hyposialylation) are the hallmark of the disease; however, the link between hyposialylation and the progressive muscle weakness characteristic of GNEM re-mains poorly understood. Whilst GNEM is not typically classified as an immune-mediated condition, some muscle biopsies revealed inflammatory and/or immune findings, including positive major histocompatibility complex class I (MHC-I) staining, a marker associated with idiopathic inflammatory myopathies. Decreased levels of SA have also been found to result in upregulated MHC-I expression, suggesting a possible immunological component. Currently, there are no European Medicines Agency (EMA) nor U.S. Food and Drug Administration (FDA) approved therapies for GNEM. In this work, we explored a possible immune mechanism in GNEM, by investigating MHC-I as a biomarker. We found that HLA-A, a gene encoding the heavy chain of MHC-I, was overexpressed in a GNE-deficient cell model. Moreover, TAP-binding protein like (TAPBPR) – a chaperone involved in MHC-I assembly – was also elevated, suggesting a potential upregulation of the MHC-I antigen presentation machinery. To further investigate the immune response under more physiologically relevant conditions, we used GNEM pa-tient-derived fibroblasts, which displayed hyposialylation. One patient sample showed high MHC-I staining, indicating the activation of immune pathways linked to antigen presentation. Additionally, treatment with a promising prodrug revealed a trend towards increased sialylation; however, no corresponding reduction in MHC-I expression was observed. These findings highlight the need for future studies involving a larger cohort of GNEM patient-derived and control fibroblasts, as well as more comprehensive glycomic analyses. Overall, this work underscores the importance of investigating immune involvement in GNEM, potentially linked to SA deficiency, as a step toward fully understanding the disease pathomechanisms and guiding the development of targeted therapies.
GNE Myopathy (GNEM) is an ultra-rare congenital disorder of glycosylation (CDG) resulting from mutations in GNE, which encodes a key enzyme in sialic acid (SA) biosynthesis. Reduced levels of SA (hyposialylation) are the hallmark of the disease; however, the link between hyposialylation and the progressive muscle weakness characteristic of GNEM re-mains poorly understood. Whilst GNEM is not typically classified as an immune-mediated condition, some muscle biopsies revealed inflammatory and/or immune findings, including positive major histocompatibility complex class I (MHC-I) staining, a marker associated with idiopathic inflammatory myopathies. Decreased levels of SA have also been found to result in upregulated MHC-I expression, suggesting a possible immunological component. Currently, there are no European Medicines Agency (EMA) nor U.S. Food and Drug Administration (FDA) approved therapies for GNEM. In this work, we explored a possible immune mechanism in GNEM, by investigating MHC-I as a biomarker. We found that HLA-A, a gene encoding the heavy chain of MHC-I, was overexpressed in a GNE-deficient cell model. Moreover, TAP-binding protein like (TAPBPR) – a chaperone involved in MHC-I assembly – was also elevated, suggesting a potential upregulation of the MHC-I antigen presentation machinery. To further investigate the immune response under more physiologically relevant conditions, we used GNEM pa-tient-derived fibroblasts, which displayed hyposialylation. One patient sample showed high MHC-I staining, indicating the activation of immune pathways linked to antigen presentation. Additionally, treatment with a promising prodrug revealed a trend towards increased sialylation; however, no corresponding reduction in MHC-I expression was observed. These findings highlight the need for future studies involving a larger cohort of GNEM patient-derived and control fibroblasts, as well as more comprehensive glycomic analyses. Overall, this work underscores the importance of investigating immune involvement in GNEM, potentially linked to SA deficiency, as a step toward fully understanding the disease pathomechanisms and guiding the development of targeted therapies.
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Palavras-chave
GNE myopathy Sialic acid Immune response MHC-I Prodrugs