Type 1 diabetes (T1D) is primarily an autoimmune disease of beta cells in the pancreatic islets and secondarily a metabolic disorder of impaired glucose metabolism due to insulin deficiency. Beta cell autoimmunity can be detected many years before the development of hyperglycaemia, providing opportunities for immune therapy to prevent T1D.
To date, islet autoantibodies are the only fully validated and clinically useful immune markers of T1D. Autoantibodies confirm the diagnosis of T1D and are risk markers for the development of T1D. However, autoantibodies are not thought to be pathogenic. In contrast, autoreactive CD4+ T cells, orchestrate autoantibody responses, and are pathogenic. The identification of T-cell biomarkers would therefore improve our understanding of T1D pathogenesis and provide opportunities to monitor responses to investigational immune therapies. Identifying such markers is challenging, however, because autoreactive T cells are rare in the blood and clinically relevant beta cell antigens and epitopes have not been defined.
This presentation will describe the CD4+ T-cell antigens we have identified by studying human islet-infiltrating CD4+ T cells. Analysis of these cells revealed that many recognized epitopes derived from proinsulin presented by HLA-DQ8. The location of these islet-infiltrating CD4+ T cells at the site of autoimmune destruction, “the scene of the crime”, their HLA-DQ8 restriction and specificity for proinsulin all point to these cells having a pathogenic role in human T1D. The application of these findings to T-cell biomarker development and the monitoring of disease progression will be discussed.