Autoantistoffer ved cøliaki: Klinisk betydning og mulige mekanismer for dannelse

Abstract

The principles of basic immunology have shown to play an important role in medicine as immunology reaches into a variety of medical fields. Through a better understanding of the pathogenesis on a molecule level, treatments in forms of immunotherapy can be established. Writing this thesis, it was therefore logical for me to present a platform of immunological theory before starting to dissect dysregulation that can take place and create autoimmunity. Coeliac disease is in a unique position with a well-established understanding of the genetic predisposition and with the driver for the disease identified, namely gluten. Thus, I will use this disease as a model to illustrate possible mechanisms underlying production of autoantibodies. With help of basic concepts, the aim is to illuminate possible mechanisms and see if they have clinical value in diagnostics. Literature were collected from a search in PubMed, and supplemented with references from the supervisor and references cited in what was my primary literature. The HLA-DQ molecules HLA-DQ2.2, HLA-DQ2.5 and HLA-DQ8 have a chief role in coeliac disease. These HLA molecules preferentially bind deamidated gluten peptides and present them to CD4+ T cells which then become activated. The gluten peptides become deamidated by the enzyme transglutaminase 2 (TG2). This enzyme can also cross-link gluten peptides including to the enzyme itself so that complexes of TG2-gluten are formed. Such TG2-gliadin complexes are the basis of a so-called hapten-carrier model which outlines that gluten specific CD4+ T cells can give help to TG2 specific B cells thereby facilitating formation of the anti-TG2 autoantibodies. This model I will discuss at length. In the first guidelines for paediatric coeliac disease was considered a food intolerance. The diagnostic scheme was based on intestinal biopsies showing alterations on elimination-provocation diets. In 2012, new guidelines were launched. In these guidelines, IgA anti-TG2 antibodies are central. As I will describe, many patients now effectively get their diagnosis on the basis of having auto-antibodies. Thus, coeliac disease has made a journey from being perceived a food intolerance disorder to being perceived an autoimmune disease. This fact illustrates very well how diagnostic approaches and medical wisdom rapidly can change