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ISSN: 1745-7580
Immunome Research
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The Role of Natural Killer Receptors in Celiac Disease

Irene Marafini1, Maria Grazia Imeneo2 and Giovanni Monteleone1*

1Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italys

2Department of Gastroenterology and Digestive Endoscopy, Università degli Studi di Catanzaro, Catanzaro, Italy

*Corresponding Author:
Giovanni Monteleone
Department of Systems Medicine, University of Rome Tor Vergata
Via Montpellier, 100133 Rome, Italy
Tel: +39.06.20903702
Fax: +39.06.72596158
E-mail: [email protected]

Received date: December 16, 2016; Accepted date: January 16, 2017; Published date: January 20, 2017

Citation: Marafini I, Imeneo MG, Monteleone G (2017) The Role of Natural Killer Receptors in Celiac Disease. Immunome Res 13: 129. doi:10.4172/1745-7580.1000129

Copyright: © 2017 Monteleone G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Celiac disease (CD) is a chronic enteropathy that develops in genetically-predisposed individuals after the ingestion of gluten. The small intestinal damage observed in CD patients is characterized by villous atrophy, crypt hyperplasia and massive infiltration of the mucosa with inflammatory cells. The molecular mechanisms that trigger and amplify inflammatory signals in CD are not fully understood. There is evidence that excessive activation of some subsets of Natural Killer (NK) cells occurs in CD and can contribute to the perpetuation of gluten-driven immune response and intestinal damage. On the other hand, the active phases of the disease are also marked by reduced mucosal presence of a specific subpopulation of NK cells expressing activating receptors and producing IL-22, a cytokine involved in the maintenance of intestinal barrier and immune homeostasis. In this article, we shortly revise the current literature on the role of NK cells in CD.


Chronic inflammatory; Hyperplasia; Viral infections


Celiac disease (CD) is a T cell-dependent chronic inflammatory disorder of the small intestine that affects approximately 1% of the population [1]. CD is triggered by ingestion of gluten, a mixture of proteins found in wheat, barley and rye, which leads to villous atrophy, crypt hyperplasia, massive infiltration of the mucosa with inflammatory cells and consequent malabsorption-related symptoms and signs [2]. The only current treatment of CD is a lifelong exclusion of gluten from the diet [2]. CD almost exclusively develops in HLA-DQ2 and/or HLA-DQ8 positive individuals, which are the restriction elements for CD4+ T cells recognizing gluten peptides [3]. The mechanisms underlying the breakdown of tolerance to gluten and the exact sequence of events leading to tissue damage in CD are not clear. Viruses could act as environmental factors promoting the development and/or propagation of CD-associated detrimental immune response. This relationship is based on the frequent observation that viral infections may precede the onset of CD [4], CD-associated inflammation is associated with increased production of interferon (IFN)-α [5], a cytokine over-produced during viral infections, and ex vivo treatment of fetal gut explants with IFN-α induces CD-like intestinal damage [6]. Support to the above hypothesis comes also from the demonstration that activation of various subsets of Natural Killer (NK) cells, a class of innate immune cells that protect host against a variety of viruses by killing infected cells, is either up-regulated or reduced in the active phases of CD [7]. NK cells exert several biological functions, including production of cytotoxic granules (i.e. granzyme B and perforin) and inflammatory or regulatory cytokines and induction antibody dependent cellular cytotoxicity [8]. Cytotoxic functions of NK cells are mainly regulated by the cell surface expression of activating and inhibitory receptors, which interact with ligands on target cells [9]. NKG2D, NKG2C, NKp44, NKp46 and NKp30 are examples of activating receptors while NKG2A in considered an inhibitory receptor [10]. Down-regulation of activating NK cell receptors is one of the strategies used by microbes to escape immune-surveillance, a phenomenon frequently observed in chronic viral infections [11]. Functional impairment of NK cells has been also described in human and experimental immune-mediated diseases (e.g. type I diabetes, encephalomyocarditis) [12], whose pathogenesis is supposed to be viral-mediated. In this context, we have recently shown that the intestinal epithelial compartment of human beings is infiltrated with distinct populations of cells expressing NK receptors and documented a different modulation of such receptors during chronic inflammation [13]. In physiological conditions, NK cells co-expressing NKp44 and NKp46, two activating receptors, produce spontaneously granzyme B and respond to toll-like receptor ligands with enhanced synthesis of granzyme B. These cell subsets are numerically reduced in inflamed duodenum of CD patients but the pathogenic relevance of such a finding remains unclear. Since NKp44/ NKp46, double-positive NK cells also produce IL-22, a cytokine involved in the maintenance of intestinal barrier and immune homeostasis, it is conceivable that this defect could contribute to perpetuate the detrimental immune response in CD. At the same time, the fact that exclusion of gluten from diet reverts NKp44/NKp46- double positive NK cell deficiency suggests that such an abnormality is not primarily involved in the initiation of the inflammatory process.

On the other hand, excessive activation of NK cells could kill epithelial cells through the perforin/granzyme pathway further contributing to the small intestinal damage [14,15]. Indeed, the active phases of the disease are characterized by increased induction of activating receptors (i.e. NKG2C, NKp30 or NKG2D) on NK cells [16]. These observations are in line with the demonstration that human major histocompatibility complex class I chain related A and B (MICA and MICB) proteins, nonconventional HLA class I molecules that serve as ligands for the activating NKG2D receptor, are over-expressed in CD patients with villous atrophy [17,18]. MICA/NKG2D interaction is supposed to mediate also killing of epithelial cells in refractory CD, a rare complication of the disease that is resistant to the gluten-free diet and can associate with the development intestinal T cell lymphoma [18].

The factors leading to upregulation of MICA proteins to the surface of enterocytes in active CD remain to be clarified. ex vivo studies with duodenal explants of CD patients on gluten-free diet show that gliadin induces MICA expression in epithelial cells through a mechanism that is dependent on interleukin (IL)-15 [14,18], a cytokine produced in excess by innate immune cells in this disorder. Consistently, the MICA-inducing effect of gliadin is reproducible by the p31-49 gliadin-derived peptide, which is able to directly activate innate immune response in CD and to induce enterocyte apoptosis, the latter effect being inhibited by a blocking IL-15 antibody [19].

Finally, CD-associated mucosal inflammation is marked by reduced levels of the inhibitory receptor NKG2A [16], which could further contribute to the NK cell-mediated intestinal epithelial injury in this disorder.

Taken together the available literature indicate that NK cells can play a major role in CD pathogenesis. While the abundance of NK cells expressing activating receptors and their ability of kill target cells support their involvement in CD-associated villous atrophy, the defective presence of NKp44/NKp46-double positive NK cells could sustain the expansion of the gluten-induced mucosal inflammation. Further studies are needed to support these hypotheses. At the moment, the limited availability of biological samples (e.g., small number of cells purified from endoscopic biopsy samples) and the lack of a valid animal model of CD-like gluten-driven tissue damage represent the major obstacles to such studies.


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