Differential IL-13 production by small intestinal leukocytes in active coeliac disease versus refractory coeliac disease

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 T(H)2 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 T(H)2 as well as T(H)1 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.

Figure 1

Production of INFγ and TNFα by IEL from active CD patients (ACD), patients on a gluten-free diet (GFD), and refractory CD type II (RCDII) patients after PMA/ionomycin/LPS stimulation. RCDII patients with villous atrophy (closed symbols); RCDII patients without villous atrophy (open symbols); for individual characteristics see Table 2. ((a), (c)) IFNγ and ((b), (d)) TNFα production. ((a), (b)) Production per 1000 IEL or ((c), (d)) per mL per two biopsies.

Figure 2

Production of (a) IFNγ, (b) TNFα, (c) IL-13, (d) IL-5, (e) IL-17, and (f) IL-10 by LPL from active CD patients (ACD), patients on a gluten-free diet (GFD), and refractory CD type II (RCDII) patients after PMA/ionomycin stimulation. RCDII patients with villous atrophy (closed symbols); RCDII patients without villous atrophy (open symbols). Groups were compared using the Mann-Whitney U test. P values are shown for significant differences.

Figure 3

Correlation between (a) IL-13 and IL-17A, (b) TNFα, (c) IL-5, (d) IFNγ and (e) IL-10 production in all groups. Correlations were tested with a two-sided Pearson correlation.