Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon γ–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.
: VSL#3 is safe and more effective than placebo in ameliorating symptoms and improving the quality of life in children affected by IBS.
Background & Aims The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to activation of intraepithelial cytotoxic T cells and development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who are without any signs of adaptive anti-gluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in absence of villous atrophy. Methods We collected blood and intestinal biopsies from 268 patients at tertiary medical centers in the US and Italy from 2004 to 2012. All subjects had had normal small intestinal histology. Study groups included healthy individuals with no family history of celiac disease or antibodies against tissue transglutamianse 2 (controls), healthy family members of patients with celiac disease, and potential celiac disease patients. Intraepithelial cytotoxic T cells were isolated and levels of inhibitory and activating natural killer (NK) cells were measured by flow cytometry. Levels of heat shock protein (HSP) and interleukin-15 (IL15) were measured by immunohistochemistry and ultrastructural alterations in intestinal epithelial cells (IEC) were assessed by electron microscopy. Results IEC from subjects with a family history of celiac disease, but not from subjects who already have immunity to gluten, expressed higher levels of HS27, HSP70, and IL15 than controls; their IEC also had ultrastructural alterations. Intraepithelial cytotoxic T cells from relatives of patients with celiac disease expressed higher levels of activating NK receptors than cells from controls, although at lower levels than patients with active celiac disease, and without loss of inhibitory receptors for NK cells. Intraepithelial cytotoxic T cells from potential celiac disease patients failed to upregulate activating NK receptors. Conclusions A significant subset of healthy family members of patients with celiac disease with normal intestinal architecture has epithelial alterations, detectable by immunohistochemistry and electron microscopy. The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with potential celiac disease.
The use of probiotics, once discussed primarily in the context of alternative medicine, is now entering mainstream medicine. However, only a few of the potential health benefits attributed to probiotics have been confirmed in well-designed, well-conducted, randomized, controlled trials. This is especially true in the pediatric population. We review here the available evidence on efficacy of probiotics in children in the prevention and treatment of gastrointestinal diseases. Although we restrict our analysis to the pediatric age, whenever potentially relevant information is available only from adult studies, they are examined as well. Probiotics have been most extensively studied in the treatment of diarrheal diseases, where their efficacy can be considered well established. Studies documenting effects in other childhood gastrointestinal illnesses are few, although some preliminary results are promising. Furthermore, only a limited number of probiotic strains have been tested, and, as the effects of different probiotic microorganisms are not equivalent, results cannot be generalized. Thus, at present, we have some positive certainties, lots of exciting promises and many unanswered questions.
IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC+ target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA2 activation and AA release. Finally, cPLA2 activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA2 activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets.
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