RESUMO
Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQß1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQß1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
Assuntos
Acalasia Esofágica/genética , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Alelos , Substituição de Aminoácidos , Estudos de Casos e Controles , Acalasia Esofágica/imunologia , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Antígenos HLA-DQ/química , Haplótipos , Humanos , Modelos Logísticos , Masculino , Modelos Moleculares , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Acalasia Esofágica/genética , Predisposição Genética para Doença/epidemiologia , Óxido Nítrico Sintase Tipo II/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Intervalos de Confiança , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/epidemiologia , Feminino , Regulação da Expressão Gênica , Humanos , Incidência , Masculino , Razão de Chances , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de RiscoRESUMO
The release of arachidonic acid (AA) in response to microorganism-derived products acting on pattern recognition receptors (PRR) was assayed in human polymorphonuclear leukocytes (PMN). Peptidoglycan (PGN) and mannan were found to be strong inducers of AA metabolism, as they produced the release of AA at a similar extent to that produced by agonists of pathophysiological relevance such as complement-coated zymosan particles and IgG immune complexes. In sharp contrast, lipoteichoic acid, LPS, muramyldipeptide, and the bacterial lipoprotein mimic palmitoyl-3-cysteine-serine-lysine-4 failed to do so. Leukotriene B4 and PGE2 were synthesized in response to mannan and PGN, thus suggesting that the lipoxygenase and the cyclooxygenase routes are operative in human PMN in response to pathogen-associated molecular patterns (PAMP). Analysis of the lipid extracts of supernatants and cell pellets as well as pharmacological studies with the calpain inhibitor calpeptin and the cytosolic phospholipase A2 (PLA2) inhibitor pyrrolidine-1 showed the dependence of AA release on cytosolic PLA2-catalyzed reactions. The effect of PGN was not inhibited by previous treatment with anti-TLR2 mAb, thus suggesting a nonarchetypal involvement of the TLR2 signaling route and/or participation of other receptors. Because of the abundance of mannose-based and PGN-containing PAMP in fungi and bacteria and the wide array of PRR in human PMN, these finding disclose a role of prime importance for PAMP and PRR in AA metabolism in the inflammatory response mediated by PMN.
Assuntos
Ácido Araquidônico/metabolismo , Mananas/farmacologia , Neutrófilos/metabolismo , Peptidoglicano/farmacologia , Antígenos de Plaquetas Humanas/metabolismo , Células Cultivadas , Citosol/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Humanos , Leucotrieno B4/metabolismo , Neutrófilos/efeitos dos fármacos , Receptores Toll-Like/metabolismoRESUMO
The induction of cyclooxygenase-2 (COX-2) and the production of PGE(2) in response to pathogen-associated molecular patterns decorated with mannose moieties were studied in human monocytes and monocyte-derived macrophages (MDM). Saccharomyces cerevisiae mannan was a robust agonist, suggesting the involvement of the mannose receptor (MR). MR expression increased along the macrophage differentiation route, as judged from both its surface display assessed by flow cytometry and the ability of MDM to ingest mannosylated BSA. Treatment with mannose-BSA, a weak agonist of the MR containing a lower ratio of attached sugar compared with pure polysaccharides, before the addition of mannan inhibited COX-2 expression, whereas this was not observed when agonists other than mannan and zymosan were used. HeLa cells, which were found to express MR mRNA, showed a significant induction of COX-2 expression upon mannan challenge. Conversely, mannan did not induce COX-2 expression in HEK293 cells, which express the mRNA encoding Endo180, a parent receptor pertaining to the MR family, but not the MR itself. These data indicate that mannan is a strong inducer of COX-2 expression in human MDM, most likely by acting through the MR route. Because COX-2 products can be both proinflammatory and immunomodulatory, these results disclose a signaling route triggered by mannose-decorated pathogen-associated molecular patterns, which can be involved in both the response to pathogens and the maintenance of homeostasis.
