RESUMEN
An increased activation of interleukin (IL)-17A-producing immune cells is a well-established feature of Crohn's disease (CD). Mechanisms that contribute to this aberrant immune activation are, however, less clear. Given that an enhanced induction of innate-immunity associated cytokines IL-6 and IL-23, which promote IL-17 immunity, is also clearly implicated in CD, we hypothesized that monocyte-derived dendritic cells (moDCs) of CD patient origin would mount exaggerated IL-17A responses in T cells. However, we found a significantly attenuated up-regulation of the IL-17A response in allogeneic T helper memory cells in the presence of culture media from lipopolysaccharide (LPS)-stimulated moDCs of CD patients when compared with moDCs of control subjects (median fold-increase in IL-17A mRNA expression 1·09 versus 1·44, P = 0·038). This was accompanied by a lower expression of IL-1ß and IL-6 transcripts in the LPS-treated moDCs (median 9·55 versus 13·9 relative units, P = 0·042, and 2·66 versus 9·06 relative units, P = 0·049, respectively). In addition, the up-regulation of autophagy-related LC3 transcripts was decreased in moDCs of CD patients (median fold-increase in mRNA expression 1·22 versus 1·52, P = 0·029). Our findings reveal similar immunological aberrancies in CD in the general population as reported in CD patients with mutated intracellular bacterial sensor NOD2, namely attenuated activation of innate cytokines and impaired autophagy, combined with a reduced capacity to up-regulate the T helper type 17 (Th17) response. The results presented here emphasize a defective anti-microbial response in the pathogenesis of CD. The increased mucosal Th1 and Th17 responses, which may contribute to the pathogenesis, could be the consequences of primary defects in the innate immunity.
Asunto(s)
Enfermedad de Crohn/inmunología , Células Dendríticas/inmunología , Proteínas Asociadas a Microtúbulos/metabolismo , Monocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Inmunidad Adaptativa , Adulto , Autofagia/genética , Autofagia/inmunología , Diferenciación Celular , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Innata , Memoria Inmunológica , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/inmunología , Activación de Linfocitos , Masculino , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Proteína Adaptadora de Señalización NOD2/genética , Adulto JovenRESUMEN
BACKGROUND: Faecal calprotectin and lactoferrin increasingly serve as surrogate markers of disease activity in IBD. Data on the correlation of these markers with simple endoscopic score for Crohn's disease (SES-CD) and with histological findings are as yet limited. Aim To study the correlation of faecal calprotectin and lactoferrin with SES-CD and histology. METHODS: During 87 consecutive ileocolonoscopies, SES-CD was calculated and biopsy specimens were obtained from the ileum, colon and rectum. Faecal calprotectin and lactoferrin were measured. RESULTS: In ileocolonic or colonic disease, both faecal calprotectin and lactoferrin correlated significantly with colon SES-CD (P < 0.001) and colon histology (P < 0.001). In patients with normal calprotectin or lactoferrin levels, endoscopic and histology scores were significantly lower than in those with elevated concentrations (P < 0.001). In ileal CD, ileal SES-CD correlated with histology (P < 0.001), but not with faecal calprotectin (P = 0.161) or lactoferrin (P = 0.448). CONCLUSION: In ileocolonic and colonic disease, endoscopic score SES-CD and histological findings correlated significantly with faecal calprotectin and lactoferrin. A normal faecal-marker concentration was a reliable surrogate marker for endoscopically and histologically inactive CD. Ileal endoscopic score and histological findings failed, however, to correlate with faecal markers.
