ROLE OF TLR PATHWAY IN THE PATHOGENESIS OF GLUTEN SENSITIVITY: PRELIMINARY STUDY

Background and aim: Reaction to gluten can involve either an allergic [wheat allergy], or non-allergic [gluten sensitivity (GS)], or an autoimmune [celiac disease (CD)] mechanism. Recent evidences suggest that early changes in intestinal permeability (IP) may play a pivotal role in the pathogenesis of CD. Conversely, no data are available on the role of IP in the pathogenesis of GS. Aims of the present progress were to investigate the changes in IP, TJ protein genes expression and TLRs in GS and to establish whether these changes are related to an over expression of inflammatory cytokines. Material and methods: Biopsy samples were obtained from 17 GS patients (pts), 27 pts with active CD, 5 pts with CD in remission, and 11 healthy controls (age range: 5-50 years). Quantitative gene expression of TJ proteins Claudin (CL) 1, CL2, CL3, CL4, ZO-1 and of TLR1, TLR2 and TLR4 were performed by Real-time PCR. IP was evaluated by lactulose/mannitol test (LA/MA). Cytofluorimetric analyses of IL6, IL8, TNFa, IFNγ were conducted on PBMC of all patients. Results: CL1, CL3 and CL4 expression were significantly increased in GS subjects compared to healthy controls, while no changes in CL2, ZO-1 and Occludin expression were detected. This up-regulation did not influence IP, since in GS patients IP (0.017±0.012) was similar to that detected in healthy controls (0.016±0.010). Conversely, in active CD patients a significant over-expression of CL1 and CL2 was observed. The increased expression of CL1/2 was associated to an increase in IP (0.202±0.55). To evaluate if the innate immune system is involved in the pathogenesis of GS, TLRs expression was measured in a subgroup of patients. TLR1, but not TLR2 and TLR4, resulted significantly increased in CD (p=0,027) and in GS (p=0,0039) in respect to normal controls. Preliminary results showed that in GS patients up-regulation of CL was associated to increased expression of IL6 and IL8. Conclusions: Compared to CD patients, GS subjects showed normal IP and CL2 expression, while the other CL tested were up-regulated. These data suggest different pathogenic mechanisms in the two conditions,i.e., in GS loss of intestinal barrier function is not involved. The over expression of TLR 1 in CD and GS could suggest an important role of innate immune system in both conditions. Gluten Sensitivity appears to be a new chapter in the book of “Food intolerance” to be investigated