Spectrum of gluten-related disorders: consensus on new nomenclature and classification

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications

ACTIVATION OF INNATE AND NOT ADAPTIVE IMMUNE SYSTEM IN GLUTEN SENSITIVITY

Background and aim: There are cases of gluten reaction defined as gluten sensitivity (GS) in which neither an allergic (wheat allergy) noran autoimmune [celiac disease (CD)] mechanism can be advocated. Recent evidences suggest that early changes in intestinal permeability (IP) and activation of both innate and adaptive immune responses are involved in CD pathogenesis. Conversely, no data are currently available on the mechanisms leading to GS. Aim was to investigate the changes in IP, TJ protein genes expression, and innate and adaptive immune responses in GS. Material and methods: Biopsy samples were obtained from 28 GS patients, 53 pts with active CD, 16 patients with CD in remission, and 37 healthy controls (age range: 5 years -50 years). Claudin (CL) 1, CL2, CL3, CL4, ZO-1, and TLR1, TLR2 and TLR4, FOXP3, and TGF-β gene expression were performed by Real-time PCR. IP was evaluated by means of the lactulose/mannitol test (LA/MA). The number of intraepithelial lymphocytes (IELs) was detected with CD3 and TCR-γδ immunostaining and examined by counting the peroxidase stained cells. ELISA analysis of IL6, IL8, TNFα, was conducted on PBMC of all patients. Results: CL3 and CL4 expressions were significantly increased in GS subjects compared to CD patients (p<0.01). In GS patients, these changes were associated to a lower IP (0.010±0.008) that inversely correlated to CL4 gene expression (r= -0.6318; p<0.05) compared to healthy controls (0.018±0.009). Conversely, in CD patients an overexpression of CL2 was observed that was associated to increased IP (0.053±0.048) and that returned to baseline following implementation of a gluten free diet. Interestingly, immunohistochemical examination of biopsy specimen showed a lower number of CD3+IELs in GS pts compared to active CD pts (27.25/100 and 36.3/100 enterocytes respectively) that correlated with MARSH 0-1 lesions, with no changes in TCR-γδ IELs. In a subgroup of GS pts, intestinal TLR1 and TLR2 expression was increased and these changes were associated to an increased production of cytokines related to the innate but not adaptive immune responses. Conclusions: Compared to CD patients, GS subjects showed normal IP and activation of the innate but not adaptive immune responses. These changes cause only minimal gut inflammation, suggesting that in GS lack of adaptive immune response involvement prevent the autoimmune gut insult typical of CD

Negri DR, Riccomi A, Pinto D, Vendetti S, Rossi A, Cicconi R, Ruggiero P, Del Giudice G, De Magistris MT

The development of mucosal vaccines for prevention of infectious diseases caused by pathogens entering through the mucosal surfaces is an important and challenging objective. To this purpose, we evaluated the efficacy and durability of immune response induced by sublingual immunization with tetanus toxoid (TT) as an antigen in the presence of mucosal adjuvants, such as E. coli Heat-Labile enterotoxin (LT) or the mutant of LT lacking ADP ribosyltransferase activity (LTK63). Both serum anti-TT IgG and mucosal anti-TT IgA antibodies reached a peak after four immunizations and decreased over time, maintaining detectable titers up to 4 months after the last immunization. Similarly, antigen-specific antibody secreting cells in bone marrow and TT-specific CD4+ and CD8+ T cells in draining lymph nodes and spleen were present up to 4 months from the last immunization. Overall, LT-treated mice showed significantly higher responses compared to LTK63 immunized mice. The efficacy and persistence of the immune response induced by sublingual immunization with different adjuvants strongly suggest that this route represents an appealing and promising alternative to the other mucosal routes of vaccine deliver

Intestinal permeability in Crohn's disease patients and their first degree relatives.

BACKGROUND: Family studies suggested that an altered intestinal permebility plays a role in the genesis of Crohn's disease. AIM: Aim of the present study was to investigate a possible genetic alteration of the mucosal barrier in Crohn's disease. SUBJECTS: 16 Crohn's disease patients and 26 of their cohabiting first degree relatives were studied. METHODS: To investigate intestinal permeability. Cellobiose/Mannitol test was administered to both groups. RESULTS: In the two groups, we found that the median intestinal permeability values were higher and statistically different from those obtained in 32 healthy control subjects as well as in five healthy control families. Six (37.5%) Crohn's disease patients and three (11.5%) of their first degree relatives showed increased individual intestinal permeability values. Intestinal permeability alteration in Crohn's disease patients was unrelated to sex, age, disease activity, localisation, duration, treatment schedule, as well as to serum anti-Saccharomyces cervisiae antibody positivity in a pilot study conducted in 7 Crohn's disease patients; anti-Saccharomyces cervisiae antobody values were negative in all 10 first degree relatives investigated. CONCLUSIONS: These findings demonstrate the increase in IP in 37% of the patients and in 11% of their relatives. More extensive investigation of the correlation between ASCA alterations and IP will be needed in both patients with Crohn's disease and their relatives

Intestinal permeability in Crohn's disease patients and their first degree

BACKGROUND: Family studies suggested that an altered intestinal permebility plays a role in the genesis of Crohn's disease. AIM: Aim of the present study was to investigate a possible genetic alteration of the mucosal barrier in Crohn's disease. SUBJECTS: 16 Crohn's disease patients and 26 of their cohabiting first degree relatives were studied. METHODS: To investigate intestinal permeability. Cellobiose/Mannitol test was administered to both groups. RESULTS: In the two groups, we found that the median intestinal permeability values were higher and statistically different from those obtained in 32 healthy control subjects as well as in five healthy control families. Six (37.5%) Crohn's disease patients and three (11.5%) of their first degree relatives showed increased individual intestinal permeability values. Intestinal permeability alteration in Crohn's disease patients was unrelated to sex, age, disease activity, localisation, duration, treatment schedule, as well as to serum anti-Saccharomyces cervisiae antibody positivity in a pilot study conducted in 7 Crohn's disease patients; anti-Saccharomyces cervisiae antobody values were negative in all 10 first degree relatives investigated. CONCLUSIONS: These findings demonstrate the increase in IP in 37% of the patients and in 11% of their relatives. More extensive investigation of the correlation between ASCA alterations and IP will be needed in both patients with Crohn's disease and their relatives

Role of the Innate Immune System in the Pathogenesis of Gluten Sensitivity : Preliminary Study

de Magistris, Alessio Fasano, Gabriele Riegler Background: Reaction to gluten can involve either an allergic (wheat allergy), or nonallergic [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: 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. Methods: After obtaining informed consent, 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 years -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 means of the lactulose/mannitol test (LA/MA). Cytofluorimetric analyses of IL6, IL8, TNFα, IFNγ were conducted on PBMC of all patients. Results: Expression of CL1, CL3 and CL4 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 CD patients a significant over-expression of CL1 and CL2 was observed, while no significant changes in the other TJ proteins were detected. The increased expression of CL1/2 was associated to an increase in IP (0.202±0.55). In CD patients in remission both IP (0.014±0.004) and CL1/2 expression returned to normal levels. 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 the GS (p=0,0039) 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