There’s a need to perform long-term follow-up studies in which the treatment duration will be significantly increased (duration of the anti-IL5 treatment in the published study was only ten weeks)

There’s a need to perform long-term follow-up studies in which the treatment duration will be significantly increased (duration of the anti-IL5 treatment in the published study was only ten weeks). Conclusion As discussed throughout this review, both innate and adaptive immune responses possibly connected by a cytokine network contribute to the immunopathogenesis of CeD. and adaptive immune pathways in distinct gut compartments are required to promote disease immunopathology. In this Fgd5 review, we will discuss how tissue destruction in the context of coeliac disease results from the complex interactions between gluten, HLA molecules, TG2, and multiple innate and adaptive immune components. or parasites such as tolerogenic T cell response to gluten is the cytokine interferon- (IFN-). IFN- is a Type-1 interferon that is produced by almost all cells as an innate response to viral infection (61). Among its many immune effector-promoting roles, it has been shown to drive pro-inflammatory dendritic cells activation as well as to promote the differentiation of CD4 T cells to the TH1 lineage (61, 62). The connection between IFN- and CeD was made by Monteleone and colleagues, who identified a CeD-like enteropathy with villous atrophy and high intraepithelial lymphocytes infiltration in a chronic myeloid leukemia patient receiving an IFN- treatment (63). The association between high expression of IFN- and high levels of IFN- in CeD patients compared to controls suggested that IFN- in CeD patients may be one factor leading to induction of a TH1 response against gluten. It remains unclear what directly is driving the increase in Docebenone IFN- production, but recent studies have also implicated viral infection as a driver for loss of oral tolerance. While viral infections, such as with adenovirus or hepatitis C, have long been known to be associated with a higher risk of developing CeD (64), only recently have viral infections been mechanistically shown to induce loss Docebenone of oral tolerance to gluten and dietary antigens. Using the Type-I Lang (T1L) reovirus strain, and murine norovirus (MNV) that both Docebenone infect the gut, Bouziat and colleagues demonstrated that both viruses were capable of mediating TH1 responses to dietary antigens (18, 19). Type-1 IFN Docebenone signaling was required for the blockade of peripheral regulatory T cells conversion while Interferon Regulatory Factor (IRF)1 expression was required Docebenone for the induction of a TH1 immunity characterized by the differentiation of IL-12p40-producing dendritic cells, the production of gluten-specific IgG2c antibodies in the serum, TG2 activation in the proximal small intestine and a delayed type hypersensitivity reaction to gluten, all hallmarks of loss of oral tolerance to gluten in virus-infected HLA-DQ8 transgenic mice (18, 19). Taken together, these studies demonstrated that viral infections can be triggers for loss of oral tolerance towards dietary antigens and TH1-skewed responses to gluten. Another major player implicated in the loss of oral tolerance to gluten is IL-15. The first signs that IL-15 may have been involved in the proinflammatory TH1 response to gluten came with the finding that IL-15 is heavily upregulated in the lamina propria of active CeD patients, the effector site where dendritic cells will encounter gluten peptides (65, 66). Using HLA-DQ8 transgenic mice that overexpressed IL-15 in the lamina propria and mesenteric lymph nodes (DQ8-Dd-IL15tg mice) but not in the intestinal epithelium (38), we demonstrated that IL-15 overexpression in combination with retinoic acid altered the tolerogenic phenotype of intestinal dendritic cells and endowed them with a pro-inflammatory phenotype, hindering the development of Foxp3+ regulatory T cells and instead promoting the differentiation of IFN-producing TH1 cells. Additionally, these gluten-fed DQ8-Dd-IL15tg mice displayed elevated levels of anti-gliadin and anti-TG2 antibodies, mimicking potential CeD patients who display a loss of oral tolerance and the development of a TH1 response to gluten in the absence of villous atrophy (38). In addition, IL-15 can block the immunosuppressive effects of TGF- on CD4 and CD8 T cells by inhibiting.