Alimentary TractGluten-free diet does not influence the occurrence and the Th1/Th17-Th2 nature of immune-mediated diseases in patients with coeliac disease
Introduction
Coeliac disease (CD) is the most common enteropathy in Western genetically susceptible subjects (HLA DQ2/DQ8) [1] mediated by a T helper cell type (Th) 1 immune response to gluten, a complex of water insoluble proteins from wheat, barley and rye [2].
Indeed, as a chronic autoimmune disorder, both innate and adaptive immune responses are involved in the pathogenesis of CD [3].
Some studies have shown how the translocation of α2-gliadin-33mer may depend on an apical-basal transcytosis stimulated by INF-γ, a cytokine involved in immunopathogenesis of CD [4]. Once it has reached the lamina propria, the gliadin would react with the tissue transglutaminase (tTG) – i.e. the enzyme catalyzing glutamine's deamidation – thus creating a transglutaminase-gliadin deamidated complex [5]. The deamidated peptide would be picked up by HLA DQ2 or DQ8 molecules on the surface of antigen-presenting cells (APC), and would be “presented” to the CD4+ T helper 1 (Th1). These Th1-cells would produce high levels of pro-inflammatory cytokines (IL2, IL6, INFγ, TNF), which could promote an increased cytotoxicity of intraepithelial lymphocytes (IELs) and natural killer (NK) T cells, causing apoptosis of enterocytes and the production of Th2 cytokines activating B cells and favoring the differentiation of plasma cells, hence resulting in the release of antibodies: anti-gliadin and anti-transglutaminase [6], [7], [8], [9].
Despite this pathogenesis, it seems that both Th1/Th17- and Th2-mediated diseases may co-exist in cases of CD [10]. It is well known that CD patients show a particular tendency for multiple autoimmune and/or allergic and/or immuno-mediated disorders (IMD) over their lifetime [11], [12], which supports this possibility.
To date, only hypotheses exist to explain the observed split in the association between the type of T lymphocyte-mediated reaction and CD. CD is frequently associated to other Th1/Th17-IMD [13], [14], [15], such as type 1 diabetes mellitus [16], autoimmune thyroiditis [17], rheumatoid arthritis [18], psoriasis [19], multiple sclerosis [20]. More recently, several studies have also shown an association between CD and some Th2-mediated disorders [15]: allergies and asthma, eczema, rhinitis [21], urticaria [22], Grave's disease [17], Sjogren syndrome [23], lichen planus [24], systemic lupus erythematosus [25].
To date, a gluten free diet (GFD) is considered the only treatment for CD. Numerous papers have investigated the effects of CD therapy on the incidence and prognosis of coexisting or subsequent IMD but thus far they have reported contradictory results [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. The aims of our study were: (1) to establish the prevalence of IMD at the time and after CD diagnosis in a large sample of adult individuals; (2) to identify any possible changes in immune response after commencement of GFD, in particular with regard to shifts from Th1/Th17- to Th2-immune response or vice versa; and (3) to investigate the potential role of GFD in reducing and/or preventing IMD in adult CD patients.
Section snippets
Methods
Between September 2011 and February 2015 we carried out a prospective study including all consecutive adult CD patients (age > 18 years) followed up at our Gastrointestinal Unit (Tertiary Centre for Food Intolerance and CD, “Federico II” University, Naples, Italy). In accordance with current guidelines, CD diagnosis was made in the presence of Marsh ≥ 2 histology associated with both anti-tissue Transglutaminase (a-tTG) IgA > 7 U/mL and positive anti-endomysial (EMA) antibodies [11]. All subjects with
Results
During the study period, 1255 CD patients referred to our Centre were enrolled (males/females 258/997). At the time of CD diagnosis, mean age + SD was 28.1 + 15.7; mean a-tTG serum level was 98.7 + 108.2 U/mL; all patients were positive for EMA. Histological exam showed a Marsh 1 grade in 64 patients (5%), Marsh 2 grade in 50 (4%), Marsh 3A in 171 (13.7%), Marsh 3B in 311 (24.8%), and Marsh 3C in 659 (52.5%). Main patient characteristics and diagnostic results are reported in Table 2.
Data collected
Discussion
At present, the only treatment for CD is represented by gluten free diet (GFD).
Numerous papers have explored the effects of GFD on the incidence and course of CD-associated IMD, often reporting contradictory results. Most of these studies, however, supported the hypothesis of a protective effect of GFD with regard to the occurrence of CD-associated IMD [12].
Our study investigated the relationship between GFD and CD-associated IMD with a specific focus on the relative prevalence of Th1/Th17- and
Conflict of Interest
None declared.
Acknowledgements
Many thanks to Giovanna Affinito, our nurse of endoscopy, for her precious support and contribution.
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2021, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :Gluten peptides that enter the lamina propria via transcytosis or paracellular routes are deamidated by tissue transglutaminase (tTG) and subsequently presented by HLA class II molecules (HLA-DQ2/8) on antigen-presenting cells (APCs) to CD4+ T cells.17–19 Inflammatory cytokines such as interferon (IFN)-γ, tumor necrosis factor (TNF) α, and interleukin (IL) 21 secreted by gluten-specific CD4+ T cells perpetuate the T-helper 1 (Th1) response and contribute to T cell–dependent B cell production of tTG and deamidated gliadin-specific antibodies.20–23 On the other hand, a non-immunodominant peptide α-gliadin 31-43, has been shown to induce an epithelial stress response24–26 and expression of IL15 by small intestinal enterocytes27 as well as lamina propria mononuclear cells.28
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2017, Digestive and Liver DiseaseCitation Excerpt :In our study, patients who continued on GCD had a statistically significant higher risk of developing CD-related IMD than patients who were placed on GFD (61% vs 18%, p = 0.03, OR = 3.3). Although the GFD does not prevent the occurrence of IMD [22], in this population the early onset of treatment could reduce the incidence, or at least delay the occurrence, of autoimmune diseases. In our opinion, our findings, along with those in the literature mentioned above, suggest that all PCD patients should start an early dietetic treatment, regardless of the presence or absence of symptoms.
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