Expression of CXCR3 axis in Celiac Disease

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

Congreso; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Celiac Disease (CD) is an immune mediated enteropathy caused by ingested gluten in genetically susceptible individuals. A lymphocytic infiltration, mainly composed by CD4+ Th1 cells, is observed in small intestinal mucosa of untreated patients. Signals for specific recruitment of these cells have not been fully established. CXCR3 is a chemokine receptor involved in cell recruitment during inflammatory processes and binds to CXCL9, CXCL10 and CXCL11. Th1 cells characteristically express CXCR3. Several reports have demonstrated an active role of CXCR3/CXCL10 axis in autoimmune processes. In previous work, we observed higher levels of circulating CXCL10, increased levels of CXCL10 and CXCL11 mRNA in duodenal samples, as well as higher numbers of CXCR3+ cells in small intestine of untreated CD patients than in controls. The aim of this work was to evaluate the CXCR3 axis in CD pathogenesis. A massive production of CXCL10 was observed in duodenal samples from untreated CD patients by confocal microscopy. CD138+ cells and enterocytes were identified as the main cellular sources of CXCL10. CXCR3+ intraepithelial lymphocytes were also observed in active CD patients. The expression of gIFN mRNA, a known inducer of CXCR3 ligands, was higher in untreated CD than in controls (p<0.0001). CXCL10 and CXCL11 mRNA expression correlated positively in CD and in non-CD mucosa and they both correlated with IFNg mRNA (p=0.0312 and p=0.0048). Duodenal biopsies incubated for three hours with the innate stimuli IL-15 or Poly I:C, showed upregulation of CXCL10 mRNA in controls (p=0.0100 and p=0.0058) but not in untreated patients. In conclusion, the massive CXCL10 production in the small intestine may be one of the main chemotactic pathways mediating Th1 cell recruitment to duodenal mucosa in active CD. CXCL10 production may also be induced by innate stimuli and consequently, it may have a role in the early events of CD pathogenesis.