Table 2.
Selected milestones and current and future research objectives in pathogenesis and genetics
| Mechanism or feature (time frame) | Milestones | Current and future research objectives |
|---|---|---|
| Cereal protein chemistry and genetics (1900s–) | Osborne66 characterized cereal grain proteins as ‘prolamins’. Starting with wheat α-gliadin, protein and gene sequencing provided key information for defining candidate toxic and/or antigenic gluten peptides67,68 | Refining understanding of a safe threshold for dietary gluten; improving food testing for gluten; breeding cereals with reduced immunogenicity; defining other cereal components that trigger symptoms; understanding gluten digestion, absorption and systemic handling in health and disease |
| Environmental antigens (1950s–) | Protease-resistant peptides from prolamins in wheat, rye, barley and, possibly, oats69 drive coeliac disease | More comprehensive molecular characterization of targets for gluten-driven immunity in all genetic subtypes of coeliac disease; triggers for disease onset; microbiome and infections as modifiers of gluten immunity and tissue injury |
| Genetic susceptibility (1970s–) | Starting with HLA associations70 and defining HLA-DQ2.5 as the primary genetic susceptibility, subsequent genome-wide studies identify multiple non-HLA linkages and genes in common with other HLA-linked autoimmune diseases such as type 1 diabetes mellitus71 | Precise localization and functional characterization of germline non-MHC genes and any additional MHC genes implicated in coeliac disease and gluten immunity; understanding gene–gene interactions, DNA modification and acquired T cell and B cell receptor mutations facilitating gluten immunity |
| Animal models, ex vivo tissue and in vitro cell culture (1970s–) | Intestinal biopsies, cell lines and clones developed as bioassays for gluten; gluten immunity tested in humanized HLA-transgenic mice from 2000s72 | Refinement of bioengineering, organoid and microfluidic technologies to develop organ-on-a-chip models to complement humanized mouse models |
| Autoimmunity in coeliac disease (1980s–) | Endomysial antibody later determined to recognize tissue transglutaminase 2, the main autoantigen for gluten-dependent autoantibodies in active coeliac disease45 | Molecular characterization of targets for autoimmunity accounting for extraintestinal manifestations; more detailed understanding of humoral and cellular autoimmunity, and its relationship to gluten immunity |
| Host receptor-mediated recognition of gluten (1990s–) | The molecular and cellular basis for recognition of gluten was determined by cloning intestinal gluten-specific CD4+ T cells exclusively from patients with coeliac disease73, which were complemented by HLA-DQ–peptide binding assays, determining epitope restriction elements and, more recently, structural biology studies9,74 | Refining understanding of gluten recognition and contributions of innate and adaptive immunity or other pathways facilitating gluten-mediated intestinal and extraintestinal manifestations of coeliac disease; expanding understanding of antigen-presenting cells including B cells specific for gluten and transglutaminase |
| Immune–intestinal epithelial cell interactions (1990s–) | Identification of crucial innate immune pathways involving IEC–NK cell receptor interactions supported by IL-15 that are conducive to atrophy75 | Characterization of the role of IEC–NK cell receptor interactions across coeliac disease states and further elucidation of signals leading to licensing of cytotoxicity |
| Extraintestinal immune response to dietary gluten (2000s–) | Gluten ingestion drives expansion of peripheral blood gut-homing gluten-reactive CD4+ T cells and CD8+ T cells days later29. Serum cytokines, especially IL-2, are elevated within hours76 | Improved characterization of the sources and effects of gluten-stimulated systemic cytokine release; understanding of the cause and effects of intestinal CD8+ T cell expansion in blood and gut tissue; establishing phenotypic and functional changes in gluten-specific CD4+ T cells |
| Additional environmental triggers (2010s–) | Resurgence of the microbial hypothesis supported by sequencing technology and longitudinal at-risk cohorts. Used in combination with humanized models, microorganisms could influence key mechanisms in coeliac disease (e.g. gluten metabolism, loss of tolerance, molecular mimicry)77 | Continued identification of microorganisms and mechanisms that protect or incite breakdown of tolerance to gluten; identify and validate new microbial therapeutics that modulate pathogenic targets in coeliac disease |
| Gluten peptide-specific activation and modulation of gluten immunity (2010s–) | Systemically administered immunogenic gluten peptides cause acute digestive symptoms and immune activation with subsequent tachyphylaxis11 | Enhanced understanding of natural mechanisms that regulate gluten immunity and disease manifestations; understanding of the basis for potential coeliac disease versus highly symptomatic disease; more complete understanding of molecular events enabling development of neoplasia associated with coeliac disease |
IEC, intestinal epithelial cell; MHC, major histocompatibility complex; NK cell, natural killer cell.