Coeliac disease is reported to affect around 1% of the western population, with ingestion of gluten typically initiating inflammation of the bowel. Current diagnostic assays based on biomarkers of gluten sensitivity are only specific for patients with classical gastrointestinal symptoms, such as those displayed in coeliac disease. However, studies have shown that gluten sensitivity can manifest with symptoms other than those related to inflammation of the bowel, notably neurological symptoms including ataxia and neuropathy. Identification of gluten sensitive patients, with a predisposition to develop neurological deficits, is crucial to prevent irreversible damage to neural tissue, as this tissue has a poor intrinsic repair capacity. A novel transglutaminase, TG6, has been discovered and shown to be predominantly expressed by a subset of neurons in the central nervous system. Furthermore, anti-TG6 IgG and IgA autoantibodies have been shown to be prevalent in gluten ataxia, independent of intestinal involvement. Therefore, TG6 antibodies have been identified as possible biomarkers to diagnose those patients that may be at risk of developing neurological disease in association with gluten sensitivity. The aim of this project was to develop a mechanistic understanding of autoantibody development and extraintestinal disease-manifestations. Specifically, the research aimed to determine whether autoantibody development to TG6 occurs in conjunction with that of TG2, i.e. in the gut, or if it has its origin in independent events. By immunofluorescent analysis of intestinal biopsies, this research was able to detect, for the first time, the presence of TG6-reactive B-cells and plasma cells in the intestinal mucosa of patients presenting with glutenrelated disorders. Additionally the research was able to identify macrophages as possible sources of TG6 at the intestinal level. These findings have led to the proposition that autoantibodies that drive the extraintestinal manifestiations of gluten related disorders are developed in the gut.