Series Introduction: Autoimmune diseases: are markers ready for prediction? (original) (raw)

This series will update our understanding of a select few organ-specific autoimmune diseases, including thyroid autoimmunity, type 1 diabetes, and CD (see the articles by Rapaport and Maclachlan, Notkins and Lernmark, and Papadopoulos et al. in this series). In all three diseases, major breakthroughs in the identification of the relevant autoantigens have allowed the development of autoantigen-specific autoantibody assays, which can be used for disease classification as well as prediction. Prediction may also be relevant to tumorigenesis, since autoantibodies that report the presence of a tumor can now be specifically detected in addition to autoantibodies in paraneoplastic disease that indirectly flag the presence of a tumor. The concept that autoimmunity can emerge from aberrant cellular growth has long been debated. A better understanding of the autoantigens involved and the development of autoantigen-specific antibody or T cell assays may help to pave the way for future clinical applications. Similarly, numerous questions remain to be answered regarding the immune responses to infection and the resulting induction of autoimmunity. For instance, would measurements of autoantibodies be useful in predicting whether an infection has placed a patient at risk of autoimmune disease?

Hashimoto thyroiditis was reported to be an autoimmune disease more than forty years ago and, together with Graves disease, has served as a model disease for the dissecting of disease pathogenesis. Hashimoto thyroiditis and Graves disease are also the most common organ-specific autoimmune diseases affecting humans, as discussed by Rapaport and Maclachlan in this series. Ironically, due to the availability of a relatively effective replacement therapy and the diseases’ onset at an older age and general lack of life-threatening complications, there has been little impetus to find a cure or develop preventative measures for these conditions. The study of Hashimoto thyroiditis and Graves disease has, however, been markedly accelerated by the identification, molecular cloning, and expression of dominant and specific autoantigens, namely thyroid peroxidase and thyrotropin receptor. While the pathogenetic role of autoantibodies against thyroid peroxidase is much debated, it now seems clear that the thyrotropin receptor antibodies can mimic the action of the thyrotropin and directly stimulate the thyroid to cause hyperthyroidism. Impressive progress is being made to identify B and T cell epitopes as well as the structural constraints of the autoantigens by ongoing crystallization efforts, but thyroid antigen uptake, processing, and presentation and the possible role of B cells in presenting autoantigen to T cells remain poorly understood. Rapaport and Maclachlan argue that the effort to identify non–HLA-contributing genes will be of little help, since even when the process of antithyroid reactivity is established, the actual mechanism by which the thyroid cells are damaged will still need to be clarified. The bottom line for these authors is that an understanding of the antigen-specific immune responses holds the key to future progress. Autoantibody assays will need to be developed and standardized using internationally recognized reference sera if they are to be used to predict thyroid disease. Unfortunately, suitable treatments for individuals who test positive for these autoantibodies are by no means obvious.

Similar unresolved issues in type 1 diabetes are also discussed by Notkins and Lernmark in this series. In type 1 diabetes it has been possible to identify three autoantigens: the smaller isoform of glutamate decarboxylase, GAD65; IA-2, also known as ICA512, an unusual transmembrane protein tyrosine phosphatase; and insulin. Much effort has been devoted to the development of standardized antibody assays in international serum-exchange workshops (8). This effort, initiated by the Immunology of Diabetes Workshops in 1985 and now continued through the effort of the Immunology of Diabetes Society in a partnership with the Center of Disease Control and Prevention, has resulted in a reference standard for both islet cell antibodies (ICAs) and GAD65 autoantibodies (3). The presence of autoantibodies to all three antigens has emerged as a strong predictor of disease. Several screening studies of newborn babies, school children, and adults, focusing in particular on first-degree relatives of affected individuals, have been carried out to test whether it is possible to reduce the risk for type 1 diabetes. In particular, nondiabetic but autoantibody-positive subjects have been administered parenteral, oral, or nasal insulin, nicotinamide, or baby formula free of cow’s-milk proteins (9).

Screening studies in newborns should help identify environmental factors that can trigger type 1 diabetes. In addition, case reports going back 100 years have shown a relationship between viral infections and type 1 diabetes, but the search for viral antigens has been de-emphasized because already at clinical onset type 1 diabetes shows signs of a chronic autoimmune disease. While it is recognized that type 1 diabetes development is strongly associated with T cells infiltrating the islets of Langerhans, a precise, reproducible, and standardized T cell assay has yet to be established. Nonetheless, the extensive work to standardize the autoantibody assays has to a very large degree made type 1 diabetes a predictable disease. The challenging next step will be to develop either refined autoantibody assays or tests of cellular immunity that show higher diagnostic sensitivity and specificity and better predictive ability than currently available autoantibody assays.

The situation in CD, as discussed by Papadopoulos et al., is somewhat different. As with thyroid disease but not type 1 diabetes, it is possible to verify the diagnosis by a biopsy of the affected tissue. In active CD, the intestinal villus is completely flattened by inflammation, but the gut regains its normal structure and absorptive function once a gluten-free diet is introduced. CD is strongly associated with certain HLA haplotypes, and since T cells in the intestinal biopsies are available for study, it has been possible for this, more than for any other, autoimmune disease to determine the role of HLA in presenting antigen-gluten to T cells. The recent demonstration that tissue transglutaminase is a CD autoantigen has generated increased interest in developing specific, sensitive radioligand assays to replace the diagnostic test that is now widely used, an immunofluorescence assay for anti-endomysial antibodies in a patient’s serum. It has been hypothesized that tissue transglutaminase modifies gluten peptides, rendering them antigenic, and that, during the course of this interaction, the enzyme itself becomes recognized as antigen. Modeling studies of HLA class II molecules with gluten peptides has provided novel insights into possible mechanisms of the structural constraints of antigen presentation. Papadopoulos et al. focus on a different question, however: Why it is only a select few of the many subjects with high-risk HLA genotypes that eventually are affected by CD? These authors (unlike Rapaport and Maclachlan in their discussion of thyroid disease) favor the search for non-HLA genetic factors, but they also consider whether we may have overlooked other, nondietary environmental factors that increase the risk of CD.