Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease

Abstract

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.

Is adaptive-innate lymphocyte cross-talk driving mucosal disease?

“…(1) are consistent with the idea that signals derived from both innate and adaptive cells regulate the activation of innate lymphocytes in nonlymphoid tissues, and thereby contribute to mucosal inflammation and disease (6,7,9,12,15,16). This lymphocyte cross-talk is an intriguing model for the amplification of adaptive immunity and raises important mechanistic questions (further information is provided in refs.…”

“…Although IL-15 is often regarded as part of an epithelial "stress response," it may have additional multifaceted roles in CD (11). A "two-hit" model of CD pathogenesis has been proposed highlighting that disease development requires both adaptive immunity and the aforementioned innate epithelial stress response to drive full activation of cytotoxic IELs and subsequent epithelial damage (12). Emphasizing the pathophysiological role of CD4 + T cells, RCDII patients are frequently homozygous for the predisposing HLA allele DQ2.5 and exhibit increased numbers of inflammatory, cytokine-producing, gluten-specific CD4 + T cells (13,14).…”

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

“…The contribution of epithelial IL-15 to CD and RCDII is well accepted (56,57); however, recent data show that IL-15 is upregulated in only a subset of CD patients (18). In addition, a sizeable subset of malignant Lin − IELs in RCDII patients express low amounts of CD122, suggesting poor IL-15 responsiveness (4).…”

“…Therefore, IL-15 was proposed to be a key therapeutic target in CD and RCDII (16,17). However, recent data show that epithelial IL-15 is up-regulated in only ∼40% of patients with active CD (18), suggesting that the contribution of IL-15 to disease varies and that other cytokines may play roles as well.…”

Transglutaminase 2-specific coeliac disease autoantibodies induce morphological changes and signs of inflammation in the small-bowel mucosa of mice

“…For instance, the mice used in the present and previous (Kalliokoski et al 2015) study lack T-cells and also the correct major histocompatibility complex (MHC) molecules, which both are relevant for the adaptive immune response in the coeliac disease pathogenesis (du Pré and Sollid 2015). In addition, innate immune activation (Kim et al 2015), structural changes in epithelial cell layer (Hüe et al 2004) and epithelial stress (Setty et al 2015) are involved in the development of the small-bowel mucosal damage in coeliac patients. Therefore, these factors along with coeliac disease antibodies might be necessary for the development of both total villous atrophy and increased permeability.…”