Analysis of the cytokine profile in the duodenal mucosa of refractory coeliac disease patients

Abstract

RCD [refractory CD (coeliac disease)] is characterized by severe symptoms/signs of malabsorption and mucosal damage unresponsive to a GFD (gluten-free diet). The pathogenesis of RCD is not fully understood. In the present paper, we have characterized the mucosal profile of effector cytokines in RCD. Duodenal biopsies were taken from patients with RCD, patients with active CD and normal controls and were analysed for inflammatory cytokines by real-time PCR and ELISA. IFN (interferon)-γ and IL (interleukin)-21 transcripts were increased in active CD patients but not in RCD patients as compared with normal controls, whereas IL-17A RNA was up-regulated in both active CD and RCD. No significant increase in IL-15 transcripts was observed in both active CD and RCD, whereas IL-15 protein was increased in active CD. IL-6 and TNF (tumour necrosis factor)-α were up-regulated only in RCD. As a proof, we present the case of a woman affected by RCD who responded to anti-TNF-α treatment with improvement of malabsorptive symptoms/signs but no healing of mucosal lesions. The findings indicate that the profile of mucosal effector cytokines differs between RCD and active CD and suggest that TNF-α, IL-6 and IL-17A, but not Th1-type cytokines, could drive the detrimental response in this condition.

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

“…The same was true for IL-15, which is not produced by T cells. In short, these findings are consistent with previous reports on the cytokine profiles of CD4 + T cells in CD (19,30,31,(33)(34)(35)(36)(37)(38)(39)(40), and identify additional cytokines produced by a gluten-specific CD4 + T-cell clone.…”

“…However, analyses of biopsy specimens support the idea that TNF, IL-2, and IL-21 are indeed produced in active CD. Experiments examining the expression of CD4 + T-cell cytokine transcripts and proteins in patient biopsy specimens and biopsy-derived gluten-specific CD4 + T cells focused on IFNG, TNF, IL2 (31, 33, 35, 36), and, more recently, on IL17, IL21, and IL22 (30,(37)(38)(39)(40). TNF, IL-2, and IL-21 were reported to be produced by gluten-activated CD4 + T-cell clones on activation (19,30,31) and to be elevated in CD biopsy specimens exposed to gluten in vivo or ex vivo (33,34,39).…”

Increased Expression of TLR4 and TLR7 but Not Prolactin mRNA by Peripheral Blood Monocytes in Active Celiac Disease

“…In in vitro studies, elevated levels of TNF-α mRNA in PBMs have been detected after gliadin stimulation [22]. In serum and duodenal mucosa, though, the available data are conflicting [23][24][25]. Lahat et al detected higher TNF-α and IL-6 mRNA expression both in intestinal mucosa and peripheral blood of active CD patients in comparison with controls.…”

Microbiome and Gluten

“…IL-17A overproduction, which is a cytokine synthesized by non-gluten-reactive CD4+ T cells and CD8+ T cells, has also been shown to be elevated at the late stage of acute CD when villous atrophy has developed, but not in potential CD or in CD patients on a GFD, suggesting that it is not primarily involved in CD [25] . This cytokine is also upregulated in refractory CD, where symptoms/signs of malabsorption and villous atrophy persist or recur after long-term adherence of a GFD, while this is not the case with Th1-type cytokines [18] . Th17 cell differentiation from naïve T cells requires the coordinated action of cytokines as those involved in the CD inflammatory process (e.g.…”

“…Additional innate immunity cytokines are overproduced in CD mucosa and supposed to amplify the inflammation and tissue-damaging response. These include IL-1 cytokine family members (IL-1β and IL-18), TNF-α and IL-6, some of which seem to be involved particularly in refractory CD cases unresponsive to a gluten-free diet (GFD) [17,18] . The increased secretion of these proinflammatory cytokines may involve the activation of innate immune signaling pathways by gluten peptides (e.g.…”