Alimentary Tract
Gluten-free diet does not influence the occurrence and the Th1/Th17-Th2 nature of immune-mediated diseases in patients with coeliac disease

https://doi.org/10.1016/j.dld.2016.03.026Get rights and content

Abstract

Introduction

Coeliac disease (CD) is the most common Th1-mediated enteropathy, frequently associated with other immune-mediated disorders (IMD).

Aims

To evaluate: (1) the prevalence of IMD at the time of and after CD diagnosis; (2) a possible change in immune response to gluten free diet (GFD); (3) the potential role of GFD in reducing and/or preventing IMD in CD.

Methods

Prospective study including all consecutive adult CD patients who underwent investigations for Th1-Th17/Th2-IMD at the time of CD diagnosis and after a 5-year follow-up period.

Results

1255 CD were enrolled. Of these, 257 patients (20.5%) showed IMD at the time of CD diagnosis, with 58.4% presenting a Th1/Th17-IMD. After a 5-year follow-up period, 682 patients (54.3%) showed new IMD despite GFD. Of these, 57.3% presented a Th1/Th17-IMD and 42.7% a Th2-IMD (p = 0.8). When compared the prevalence of each type of IMD before and after CD diagnosis, we did not identify any significant “switch” from Th1/Th17- to Th2-IMD or vice versa. The number of patients with Th1/Th17- and/or Th2-IMD increased during the GFD period (20.5% vs 54.3%; p < 0.01; OR 1.9).

Conclusions

The prevalence of IMD at the time of CD diagnosis is high and it seems to increase in the follow-up period despite GFD.

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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