Role of dendritic cells in the induction and maintenance of autoimmune diseases

Autoimmune diseases are characterised by the loss of tolerance against self -determinants, activation of autoreactive lymphocytes and pathological dama ge to single or multiple organs. The mechanisms by which autoimmune respons es are triggered and activation of autoreactive lymphocytes is initiated an d maintained are not yet fully understood. Translocation of previously immu nologically ignored antigens from the periphery to secondary lymphoid organ s is probably a key step in the initiation of autoimmunity. Antigen transpo rt and primary sensitisation of T lymphocytes is mainly mediated by dendrit ic cells which reside in peripheral non-lymphoid tissues and maintain a con tinuous gradient of antigens towards secondary lymphoid tissues. In the tra nsgenic rat insulin promoter-glycoprotein model of autoimmune diabetes, den dritic cell (DC)mediated antigen transport: initiates an autoimmune respons e against a pancreatic neoself-antigen. Dose and timing of antigen delivery by DC and turnover of antigenic peptides presented by DC are the main para meters regulating the outcome of autoimmune diabetes in this model system. An important sequel of continued antigenic stimulation via DC is the format ion of lymphoid structures in the pancreas. Thus, appropriate and repeated activation of cytotoxic T lymphocytes by DC, in concert with local inflamma tory processes leading to formation of organised lymphoid tissue in the tar get organ, is likely to be crucial in the development of destructive autoim munity. Therapeutic intervention to selectively manipulate antigen transpor t by dendritic cells or to influence antigen presentation may prove benefic ial for the treatment of autoimmune diseases. Furthermore, the capacity of DC to induce potent antiself responses might have implications for the use of DC presenting self-antigens in treatment of established tumours.