CXCR3 / CXCL10 axis in intestinal mucosa in active coeliac disease

BONDAR, CONSTANZA; GUZMAN, LUCIANA; CUETO RUA, EDUARDO; CHOPITA, NÉSTOR; CHIRDO, FERNANDO

Encuentro; 26th meeting of Working Group on Prolamin Analysis and Toxicity; 2012

Coeliac disease (CD) is a chronic small intestinal inflammatory condition induced by an inappropriate immune response to dietary gluten. Priming of gluten-specific naive T cells occurs in organised lymphoid tissue, likely in the mesenteric lymph nodes, whereas the activation and expansion of these cells take place in the small intestine lamina propria by antigen presenting cells. Majority of gluten specific T cells are Th1 cells, and consequently γIFN producer. Cell migration into the small intestine mucosa requieres different signals from two main systems that guide this process. Expression of adhesion molecules in the endothelial cells, the best example is MadCAM1, and the expression of α4β7 in lymphoid cells allow the migration of cells out of the blood vessels into the tissue. Inside the tissue, chemokines guide the cells to the site of inflammation. The CXCL10/CXCR3 axis is one of the main factors controlling the cell recruitment under an inflammatory process, as it was reported for chronic inflammatory process such as autoimmunity (type 1 diabetes, reumatoid arthritis) IFNγ is the stronger inducer of CXCL10 expression. CXCL10 is produced by CD4+ T cells, NK and NKT cells, monocytes, dendritic cells, neutrophils, fibroblasts [6]. Remarkably, synoviocytes and β cells, actively produce CXCL10 during the inflammatory process, arthritis or insulitis, respectively. CXCL10 interacts with CXCR3, which is expressed by T lymphocytes, NK cells, eosinophils, monocytes, B lymphocytes, plasma cells. Particularly, Th1 cells are CXCR3+ cells. CXCR3 interacts not only with CXCL10 but also with CXCL9 and CXCL11. These chemokines are differentially expressed in different pathological conditions suggesting that they have non-redundant biological functions. The aim of this work was to investigate the role of CXCR3 and its ligands in CD pathogenesis. CXCL10 is overproduced in the duodenal mucosa in active CD. Moreover, we demonstrated that the number of CXCR3+ cells is increased in the mucosa of active CD compared with control or treated CD patients. The massive CXCL10 production in the small intestine may be one of the main chemotactic pathways mediating the recruitment of T cells, particularly Th1 CD4+ T cells and plasma cells. Our results suggest that CXCL10 may be also a biomarker for disease activity since CXCL10 levels in serum are significantly higher in untreated patients than in control population. Altogether these findings highlight the relevance of the CXCR3/CXCL10 axis in CD pathogenesis.