Tolerance and Autoimmunity in Type 1 Diabetes

Abstract

A functional immune system is able to distinguish between foreign antigens expressed by pathogens and self-antigens expressed by the body. The absence of a pathological response to self-antigens (e.g. tolerance) is dependent on a number of events that occur both centrally and peripherally. Central tolerance is induced at sites of lymphocyte development such as thymus and bone marrow for T cell and B cell respectively. On the other hand, peripheral tolerance occurs at sites of antigen recognition and processing, and includes secondary lymphoid as well as non-lymphoid tissues. Failure of central and/or peripheral tolerance can lead to increased development and expansion of pathogenic effector T cells and subsequent initiation and progression of autoimmunity. Type 1 Diabetes (T1D) is an autoimmune disease due to a chronic inflammation in the pancreas that leads to the destruction of insulin-producing -cells. The -cells are selectively destroyed via both direct and indirect mechanisms by different immune cell types. Studies in animal models and humans have demonstrated that T cells play a major role in -cell death. However, other cell types are present in the pancreatic infiltrate and in the pancreatic lymph node, where the initial presentation of islet antigen by dendritic cells (DC) to islet antigen specific T cells occurs. Besides different DC subsets, B cells and natural killer (NK) cells also contribute, with different roles, to -cell destruction. This suggests a strong crosstalk between the immune cells that are involved in pathogenesis and those involved in immune regulation. Herein, we will describe the autoimmune processes that result in clinical manifestation of this disease and we will discuss the immunologic basis supporting possible new therapeutic interventions.