Contribution of Infectious Agents to the Development of Celiac Disease

Abstract

The ingestion of wheat gliadin (alcohol-soluble proteins, an integral part of wheat gluten) and related proteins induce, in genetically predisposed individuals, celiac disease (CD), which is characterized by immune-mediated impairment of the small intestinal mucosa. The lifelong omission of gluten and related grain proteins, i.e., a gluten-free diet (GFD), is at present the only therapy for CD. Although a GFD usually reduces CD symptoms, it does not entirely restore the small intestinal mucosa to a fully healthy state. Recently, the participation of microbial components in pathogenetic mechanisms of celiac disease was suggested. The present review provides information on infectious diseases associated with CD and the putative role of infections in CD development. Moreover, the involvement of the microbiota as a factor contributing to pathological changes in the intestine is discussed. Attention is paid to the mechanisms by which microbes and their components affect mucosal immunity, including tolerance to food antigens. Modulation of microbiota composition and function and the potential beneficial effects of probiotics in celiac disease are discussed.

Keywords: celiac disease; gluten-free diet; immune response; infections; microbiota; parasites.

Figure 1

Key characteristics of celiac disease pathogenesis. Impairment of mucosal barrier of small intestine and penetration of food antigens, including wheat gliadin. Gliadin fragments are deamidated by tissue transglutaminase. Deamidated gliadin fragments stimulate (boosted by adjuvant properties of microbiota) innate immune cells, counting professional antigen presenting cells (dendritic cells), which present deamidated gliadin peptides by CD4⁺T cells. Polarization of CD4⁺T lymphocyte development to Th1 cytokine profile leads to activation (intraepithelial) lymphocytes and damaging of enterocytes. Activation of fibrocytes by Th1 cytokines trigger releasing of matrix metalloproteinases mediating pathological remodeling of small gut mucosa of celiac patients. Simultaneously, antibodies against gliadin and autoantibodies against tissue transglutaminase are developed.

Figure 2

Involvement of infections and dysbiosis in pathogenesis of celiac disease. Infectious components possess the capability to non-specifically stimulate the immune system via: (1) adjuvant properties of bacterial and viral molecules; (2) stimulation of expression of classical and non-classical MHC molecules; (3) stimulation of antigen presentation, including cross-presentation of gliadin and autoantigens; (4) capacity of cross-reactivity of adaptive immune cells induced by mechanism of “molecular mimicry”; and (5) disruption of gut mucosal barrier leading to increased intestinal permeability for luminal food and bacterial antigens and thus elevated antigenic load in mucosal layer of small intestine.