RESUMEN
Ulcerative colitis (UC) is characterized by chronic intestinal inflammation. Patients with UC have repeated remission and relapse. Clinical biomarkers that can predict relapse in UC patients in remission have not been identified. To facilitate the prediction of relapse of UC, we investigated the potential of novel multivariate indexes using statistical modeling of plasma free amino acid (PFAA) concentrations. We measured fasting PFAA concentrations in 369 UC patients in clinical remission, and 355 were observed prospectively for up to 1 year. Relapse rate within 1 year was 23% (82 of 355 patients). The age- and gender-adjusted hazard ratio for the lowest quartile compared with the highest quartile of plasma histidine concentration was 2.55 (95% confidence interval: 1.41-4.62; p = 0.0020 (log-rank), p for trend = 0.0005). We demonstrated that plasma amino acid profiles in UC patients in clinical remission can predict the risk of relapse within 1 year. Decreased histidine level in PFAAs was associated with increased risk of relapse. Metabolomics could be promising for the establishment of a non-invasive predictive marker in inflammatory bowel disease.
Asunto(s)
Colitis Ulcerosa/sangre , Histidina/sangre , Adulto , Biomarcadores/sangre , Colitis Ulcerosa/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Factores de RiesgoRESUMEN
BACKGROUND: In Crohn's disease (CD), the involvement of food antigens in immune responses remains unclear. The objective of this study was to detect immune responses against food antigens in CD patients and examine the mechanism in a mouse model of colitis. METHODS: We enrolled 98 CD patients, 50 ulcerative colitis patients, and 52 healthy controls (HCs) to compare the levels of serum immunoglobulin (Ig)Gs against 88 foods. The presence of serum IgGs against foods was also examined in interleukin (IL)-10 knockout (KO) mice in which CD4(+) T cell activation by antigenic food protein was assessed. Mice transferred with IL-10 KO cells received diets with or without food antigens, and the development of colitis was evaluated. RESULTS: The prevalence of IgGs against various foods, especially vegetables, grains, and nuts, was significantly higher in CD patients than in HCs. Similarly, the prevalence of IgGs against food proteins was higher in IL-10 KO mice than in BALB/c mice. Beta-conglycinin, identified as an antigenic food proteins in IL-10 KO mice, induced CD4(+) T cell production of interferon-γ and IL-17 through dendritic cell antigen presentation. Elimination of the food antigens ameliorated the development of colitis in mice without altering the composition of their intestinal microbiota. CONCLUSIONS: In CD colitis mice, intestinal inflammation via CD4(+) T cell hyperactivation was induced by food antigens associated with high serum IgG levels and was ameliorated by the elimination of food antigens. This disrupted immunological tolerance to food antigen, which might act as an exacerbating factor, remains to be elucidated in CD patients.
Asunto(s)
Colitis/inmunología , Enfermedad de Crohn/inmunología , Hipersensibilidad a los Alimentos/inmunología , Adolescente , Adulto , Anciano , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Células Cultivadas , Colitis/complicaciones , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/complicaciones , Modelos Animales de Enfermedad , Femenino , Hipersensibilidad a los Alimentos/complicaciones , Humanos , Inmunoglobulina G/sangre , Interleucina-10/deficiencia , Interleucina-10/genética , Activación de Linfocitos/inmunología , Masculino , Ratones Endogámicos BALB C , Ratones Noqueados , Persona de Mediana Edad , Adulto JovenRESUMEN
Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (MÏs) and dendritic cells. MÏs differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-MÏs), which are similar to the human intestinal lamina propria CD14(+) MÏs that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated MÏ and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-MÏs stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14(+) intestinal MÏs from patients with CD expressed TGR5. In isolated intestinal CD14(+) MÏs, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.
Asunto(s)
Enfermedad de Crohn/inmunología , Citocinas/inmunología , Regulación de la Expresión Génica/inmunología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Receptores Acoplados a Proteínas G/inmunología , Transducción de Señal/inmunología , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Células Cultivadas , Colagogos y Coleréticos/farmacología , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Enfermedad de Crohn/terapia , Citocinas/biosíntesis , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/patología , Ácido Desoxicólico/farmacología , Detergentes/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interferón gamma/farmacología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Lipopolisacáridos/farmacología , Ácido Litocólico/farmacología , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Proteínas Proto-Oncogénicas c-fos/inmunología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/biosíntesis , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/inmunología , Factor de Transcripción ReIA/metabolismoRESUMEN
BACKGROUND: Chronic inflammation characterised by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC); however, whether its function is pathogenic or protective remains unclear. OBJECTIVE: To explore the contribution of intestinal IgG plasma cells to UC pathogenesis. METHODS: We isolated lamina propria mononuclear cells (LPMCs) from intestinal mucosa of UC patients and analysed the characteristics of intestinal plasma cells (expression profiles of differentiation molecules and chemokine receptors). We investigated the involvement of IgG-immune complex (IC)-Fc gamma receptor (FcγR) signalling in intestinal inflammation by examining the cytokine production by LPMCs in response to IgG-IC stimulation. RESULTS: IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CD19(+)CD27(low), CCR10(low)CXCR4(high)) compared with IgA plasma cells (CD19(+/-)CD27(high), CCR10(high)CXCR4(-/low)). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via FcγRI and FcγRII, and induced the extensive production of pro-inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1ß (IL-1ß), comparable to the effect of commensal bacteria stimulation. Co-stimulation with IgG-IC and commensal bacteria increased TNF and IL-1ß production more than stimulation with the latter alone. Furthermore, IgG-IC notably up-regulated the expression of TL1A, whereas commensal bacteria specifically induced IL-23. CONCLUSIONS: Collectively, these results demonstrate a novel aspect of UC pathogenesis in which unique IgG plasma cells infiltrate the inflamed mucosa via CXCR4, and critically influence UC pathogenesis by exacerbating mucosal inflammation through the activation of 'pathogenic' intestinal CD14 macrophages via IgG-IC-FcγR signalling.
Asunto(s)
Colitis Ulcerosa/etiología , Activación de Macrófagos/inmunología , Células Plasmáticas/fisiología , Receptores CXCR4/fisiología , Receptores de IgG/fisiología , Colitis Ulcerosa/inmunología , Citocinas/inmunología , Citocinas/fisiología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/fisiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/fisiología , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/fisiología , Activación de Macrófagos/fisiología , Células Plasmáticas/inmunología , Receptores CXCR4/inmunología , Receptores de IgG/inmunología , Transducción de Señal/inmunología , Transducción de Señal/fisiología , Transcriptoma/fisiologíaRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram). METHODOLOGY AND PRINCIPAL FINDINGS: We measured fasting plasma aminograms in 387 IBD patients (Crohn's disease (CD), nâ=â165; ulcerative colitis (UC), nâ=â222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, nâ=â102; UC, nâ=â102; age and sex-matched healthy controls, nâ=â102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898-0.983) and 0.894 (95%CI: 0.853-0.935), respectively in validation samples (CD, nâ=â63; UC, nâ=â120; healthy controls, nâ=â108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853-0.935) and 0.849 (95%CI: 0.770-0.928), and correlated with clinical disease activity indexes for CD (r(s)â=â0.592, 95%CI: 0.385-0.742, p<0.001) or UC (r(s)â=â0.598, 95%CI: 0.452-0.713, p<0.001), respectively. CONCLUSIONS AND SIGNIFICANCE: In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.