Extended Data Fig. 9: Model for ameloblast-specific autoantibody production in patients with coeliac disease.

Illustration of the proposed model for ameloblast-specific autoantibody production in patients with coeliac disease. The inflamed environment of the small intestine in patients with coeliac disease disrupts intestinal barrier capacity and increases intestinal permeability (i.e., leaky gut). This results in generation of antibodies to various food antigens with high immunogenicity (e.g., gliadins or caseins). Reactivity to food antigens is often accompanied by epitope and antigen spreading and subsequent production of autoantibodies to various proteins expressed in the intestinal microenvironment (e.g., TGM2 and LAMB3) (1). The plasma cells and/or autoantibodies are then transferred via the bloodstream to the developing enamel matrix where they can bind to their targets expressed in the dental tissues and enamel matrix (2). The opsonized enamel autoantigens can then be internalized by dental macrophages (and possibly other resident phagocytes), which serve as local sentinels and bind these autoantibodies via their FCGR/FCAR receptors expressed on the surface of these cells (3). Such interactions facilitate the internalization of the antibody-self-antigen complexes by the phagocytes (4). The engulfed antigens will then be presented by the phagocytes on their MHCII molecules in the context of inflammation to self-reactive T cell escapees that are normally kept in check by peripheral mechanisms of self-tolerance. This further potentiates the formation of the adaptive immune response, including further antibody formation and epitope spreading to enamel-specific proteins, in a self-perpetuating mechanism. Illustration was created with BioRender.com.