Abstract
A small fraction of coeliac disease (CD) patients have persistent villous atrophy despite strict adherence to a gluten-free diet. Some of these refractory CD (RCD) patients develop a clonal expansion of lymphocytes with an aberrant phenotype, referred to as RCD type II (RCDII). Pathogenesis of active CD (ACD) has been shown to be related to gluten-specific immunity whereas the disease is no longer gluten driven in RCD. We therefore hypothesized that the immune response is differentially regulated by cytokines in ACD versus RCDII and investigated mucosal cytokine release after polyclonal stimulation of isolated mucosal lymphocytes. Secretion of the TH2 cytokine IL-13 was significantly higher in lamina propria leukocytes (LPLs) isolated from RCDII patients as compared to LPL from ACD patients (P = 0.05). In patients successfully treated with a gluten-free diet LPL-derived IL-13 production was also higher as compared to ACD patients (P = 0.02). IL-13 secretion correlated with other TH2 as well as TH1 cytokines but not with IL-10 secretion. Overall, the cytokine production pattern of LPL in RCDII showed more similarities with LPL isolated from GFD patients than from ACD patients. Our data suggest that different immunological processes are involved in RCDII and ACD with a potential role for IL-13.
Highlights
Coeliac disease (CD) is an autoimmune enteropathy that is triggered by the gliadin fraction of dietary gluten peptides [1]
A total of 20 patients were included in our study: 4 patients with active coeliac disease (ACD), 7 on a glutenfree diet (GFD), and 9 patients with RCD type II (RCDII)
The follow-up time of GFD patients was at least 8 months, and that of RCDII patients at least 2 years since the start of the gluten-free diet
Summary
Coeliac disease (CD) is an autoimmune enteropathy that is triggered by the gliadin fraction of dietary gluten peptides [1]. Gliadins can exert direct toxic effects by binding to epithelial cells, resulting in the production of IL-15 and TNFα [3,4,5]. The main pathogenic mechanism of CD, is believed to be a gluten-specific TH1-mediated response resulting in an overexpression of IFNγ in the (intra) epithelial compartment [7]. TG2 binds and deamidates gliadin peptides, which leads to a better presentation of gliadin peptides to specific TH cells and a subsequent stronger gliadin-specific immune response with even higher amounts of IFNγ [9, 10]. The exact mechanism is unknown, evidence exists that the overexpressed IFNγ leads to the mucosal damage found in CD [11, 12]. In a pilot phase I study, treatment with recombinant IL-10 did induce some relief of symptoms in a minority of patients but IL-10 treatment did not lead to mucosal recovery [15]
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