Triggers and drivers of autoimmunity: lessons from coeliac disease

Abstract

Coeliac disease, an inflammatory disease of the small intestine, shares key features with autoimmune disorders, such as susceptibility genes, presence of autoantibodies and T cell-mediated destruction of specific cells. Strikingly, however, continuous exposure to the exogenous dietary antigen gluten and gluten-specific adaptive immunity are required to maintain immunopathology. These observations challenge the notion that autoimmunity requires adaptive immune activation towards self antigens. Using coeliac disease as an example, we propose that other exogenous factors might be identified as drivers of autoimmune processes, in particular when evidence for T cells with specificity for self antigens driving the disease is lacking.

Figure 1. Autoimmune phenomena and adaptive anti-gluten immunity are associated with coeliac disease and are dependent on gluten exposure

Coeliac disease pathology is characterised by the presence of gluten-specific adaptive immunity and the presence of autoimmune phenomena such as cytotoxic autoantibodies and CD8⁺ T cells that mediate enterocyte destruction without being gluten specific. Autoimmune and non auto-immune phenomena, as well as tissue pathology, recede when dietary gluten is eliminated and reoccur when gluten is reintroduced.

Figure 2. Coeliac disease and autoimmune disorders share many common immune mechanisms

MHC class II molecules, post-translational modifications (PTM), autoantibodies (auto-Ab), IL-15, IFN-α, T helper 1 (T_H1) type immunity, IL-21, natural killer cell receptors (NKRs) and non-classical MHC class I molecules have been reported to be implicated in many autoimmune disorders.

Figure 3. Dietary antigen drives autoimmune processes in coeliac disease

Triggers such as viruses, pathogens and pathobionts activate antigen-presenting cells and epithelial cells. Antigen-presenting cells acquire proinflammatory properties and present gluten to induce the activation of gluten-specific HLA-DQ2- or HLA-DQ8-restricted CD4⁺ T cells. Because transglutaminase 2 (TG2) and gluten form complexes, TG2-specific autoreactive B cells internalize TG2–gluten complexes and present gluten peptides on HLA-DQ2 or HLA-DQ8 at their surface. Gluten-specific B cells can bind and present deamidated gluten peptides in a conventional manner. The gluten-specific CD4⁺ T cells provide help to both autoreactive TG2-specific and gluten-specific B cells, which will differentiate into antibody producing plasma cells. Activated gluten-specific CD4⁺ T cells also provide signals (that remain to be fully defined) to pre-activated epithelial cells, which upregulate IL-15 and non-classical MHC class I molecules. Consequently, intraepithelial cytotoxic T lymphocytes (IE-CTLs) acquire lymphokine activated killer activity and a decreased T cell receptor (TCR) activation threshold and will kill epithelial cells based on the recognition of stress signals. Whether IE-CTLs with a decreased TCR activation threshold will recognise low affinity epithelial antigens and antigens of the microbiota through their TCR remains to be determined. The autoimmune phenomena are boxed.