RESUMO
BACKGROUND: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunizations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation. Peripheral blood mononuclear cells from respiratory infection allergy/asthma-prone (IAP) infants and non-infection allergy/asthma prone (NIAP) were retrospectively selected for genome-wide DNA methylation and single nucleotide polymorphism analysis. The IAP infants were enriched for the low vaccine responsiveness (LVR) phenotype (Fisher's exact p-value = 0.02). RESULTS: An endotype signature of 813 differentially methylated regions (DMRs) comprising 238 lead CpG associations (FDR < 0.05) emerged, implicating pathways related to asthma, mucin production, antigen presentation and inflammasome activation. Allelic variation explained only a minor portion of this signature. Stimulation of mononuclear cells with monophosphoryl lipid A (MPL), a TLR agonist, partially reversed this signature at a subset of CpGs, suggesting the potential for epigenetic remodeling. CONCLUSIONS: This proof-of-concept study establishes a foundation for precision endotyping of IAP children and highlights the potential for immune modulation strategies using adjuvants for future investigation.
Assuntos
Asma , Metilação de DNA , Epigênese Genética , Leucócitos Mononucleares , Infecções Respiratórias , Humanos , Asma/genética , Asma/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Metilação de DNA/genética , Masculino , Feminino , Infecções Respiratórias/imunologia , Infecções Respiratórias/genética , Lactente , Epigênese Genética/genética , Polimorfismo de Nucleotídeo Único , Ilhas de CpG/genética , Estudos Retrospectivos , Estudo de Associação Genômica Ampla/métodos , Pré-Escolar , Criança , Estudo de Prova de ConceitoRESUMO
Background: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunisations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation. Peripharal immune cells from respiratory infection allergy/asthma prone (IAP) infants were retrospectively selected for genome-wide DNA methylation and single nucleotide polymorphism analysis. The IAP infants were enriched for the low vaccine responsiveness (LVR) phenotype (Fishers Exact p-value = 0.01). Results: An endotype signature of 813 differentially methylated regions (DMRs) comprising 238 lead CpG associations (FDR < 0.05) emerged, implicating pathways related to asthma, mucin production, antigen presentation and inflammasome activation. Allelic variation explained only a minor portion of this signature. Stimulation of mononuclear cells with monophosphoryl lipid A (MPLA), a TLR agonist, partially reversing this signature at a subset of CpGs, suggesting the potential for epigenetic remodelling. Conclusions: This proof-of-concept study establishes a foundation for precision endotyping of IAP children and highlights the potential for immune modulation strategies using adjuvants for furture investigation.