Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies

Abstract

Our understanding of celiac disease and how it develops has evolved significantly over the last half century. Although traditionally viewed as a pediatric illness characterized by malabsorption, it is now better seen as an immune illness with systemic manifestations affecting all ages. Population studies reveal this global disease is common and, in many countries, increasing in prevalence. These studies underscore the importance of specific HLA susceptibility genes and gluten consumption in disease development and suggest that other genetic and environmental factors could also play a role. The emerging data on viral and bacterial microbe-host interactions and their alterations in celiac disease provides a plausible mechanism linking environmental risk and disease development. Although the inflammatory lesion of celiac disease is complex, the strong HLA association highlights a central role for pathogenic T cells responding to select gluten peptides that have now been defined for the most common genetic form of celiac disease. What remains less understood is how loss of tolerance to gluten occurs. New insights into celiac disease are now providing opportunities to intervene in its development, course, diagnosis, and treatment.

Keywords: T cells; celiac disease; gluten; microbiome; pathogenesis.

Figure 1

Key steps in CeD pathogenesis. Gluten peptides containing T-cell epitopes resist gastrointestinal degradation. tTG catalyses the deamidation of gluten peptides, which can then bind more efficiently to the disease-relevant HLA-DQ molecules on APCs. Activated gluten-specific CD4+ T cells secrete a variety of pro-inflammatory cytokines such as IFN-γ and IL-21 that contribute to the intestinal lesion and promote activation of IELs and stimulate B-cell responses. Activated IELs transform into cytolytic NK-like cells that mediate destruction of enterocytes expressing stress signals. IL-15 renders effector T cells resistant to the suppressive effects of Tregs and, in the lamina propria, endows mucosal DCs with inflammatory properties promoting pro-inflammatory responses and preventing Treg differentiation.

Figure 2

Potential role of microbes and environmental triggers in CeD pathogenesis. Microbes that include both commensals and opportunistic pathogens may contribute to the development of CeD by influencing gluten peptide digestion, intestinal barrier function, epithelial cell stress, or IEL activation/upregulation through IL-15 regulation. Pathogenic bacteria, viruses, and non-gluten components of wheat, such as amylase-trypsin inhibitors (ATIs), may also induce DC maturation and proinflammatory cytokine production, modulating the induction of CD4+ T-cell responses.