Toll-like receptors and their role in the development of autoimmune diseases

Human Toll-like receptors (TLRs) are crucial for the recognition of invading pathogens and for the activation of both innate and adaptive immunity. Upon stimulation, TLRs recruit various protein kinases via several adaptor molecules, such as MyD88, leading to the activation of NFkB. The identification of TLR signaling pathways may unravel molecular mechanisms of self-tolerance and the means underlying the development of autoimmunity. The maturation of antigen-presenting cells (APCs), in response to signals received by the innate immune system, may lead to the breakdown of tolerance. This process is mainly activated by TLRs that have been triggered by self-antigens. Auto-reactive B cells are present in the lymphoid tissues of healthy individuals, but since they are subject to self-tolerance mechanisms, they remain silent. However, when tolerance to self-antigens fails, a complex of self-reactive antibodies against self- or cross-reactive DNA co-engages the antigen receptor and the TLRs, leading to a continuous activation of these auto-reactive B cells and the development of autoimmune diseases. The contribution of TLRs to the production of auto antibodies by such dual-engagement suggests that this signaling pathway may become a target for new therapeutic approaches in autoimmune diseases.