Protective role of anti-idiotypic antibodies in autoimmunity--lessons for type 1 diabetes.

Circulating autoantibodies to beta cell antigens are present in the majority of patients with Type 1 diabetes. These autoantibodies can be detected before and at time of clinical diagnosis of disease. Although the role of autoantibodies in the pathogenesis of the disease is debated, their presence indicates a dysregulation of the humoral immune response. Mechanisms regulating autoantibodies in Type 1 diabetes are not well understood. In contrast, in other autoimmune diseases there is acceptance that autoantibodies are regulated not only by antigen but also by other antibodies that bind to the antigen-binding site of these autoantibodies (anti-idiotypic antibodies). The proposed purpose of this network is to maintain an equilibrium between autoantibodies and their anti-idiotypic antibodies, preventing autoimmunity, while allowing a robust response to exogenous antigen. Anti-idiotypic antibodies regulate both autoantibody binding and their levels by a) neutralizing autoantibodies, and b) inhibiting the secretion of autoantibodies. Because it has been proposed that the B lymphocytes that produce autoantibodies function as autoantigen presenting cells, inhibiting their binding to autoantigen by anti-idiotypic antibodies may prevent development of autoimmune disease. This hypothesis is supported by the presence of anti-idiotypic antibodies in healthy individuals and in patients in remission from autoimmune diseases, and by the lack of anti-idiotypic antibodies during active disease. We recently reported the presence of autoantibodies to glutamate decarboxylase in the majority of healthy individuals, where their binding to autoantigen is prevented by anti-idiotypic antibodies. These anti-idiotypic antibodies are absent at clinical diagnosis of Type 1 diabetes, revealing the presence of autoantibodies. Type 1 diabetes (T1D) is an autoimmune disease characterized by the dysfunction and destruction of insulin-producing beta cells by autoreactive T cells. Although much progress has been made towards understanding the respective roles of effector and regulatory T cells in this beta cell destruction, the development of autoantibodies to beta cell proteins is widely considered simply a by-product of the autoimmune destruction of the beta cells, rather than having an active role in the pathogenesis. This view is starting to change based on increasing recognition that autoantibodies can have defined roles in other autoimmune diseases, and the emergence of new data on their role in T1D. This exploration of the role of autoantibodies in autoimmune disease has been spurred, in part, by increasing recognition that development of autoimmune diseases is influenced by regulatory antibodies (anti-idiotypic antibodies) directed against the unique binding site of autoantibodies. This review provides an overview of the development and function of these anti-idiotypic antibodies, and present evidence supporting their role in the development of autoimmune diseases. Finally, we conclude this review with a model of the events that may cause loss of anti-idiotypic antibodies and the implications for the development of T1D.