Interfering With Dendritic Cell Functions

Dendritic cells contribute to central tolerance in the thymus by presenting antigens to T cells and deleting the T cells that exhibit strong autoreactivity. However, dendritic cells also play a pivotal role in peripheral tolerance. In the absence of infection or inflammation, dendritic cells remain immature and capture antigens via a number of mechanisms, such as phagocytosis and macropinocytosis (31). These immature dendritic cells contribute to deleting autoreactive lymphocytes and to expanding the population of regulatory T cells, thereby ensuring peripheral tolerance. Dendritic cells mature when they come into contact with antigen via surface receptors called Toll-like receptors (TLR) and via receptors belonging to the TNF family (TNFa and CD40 ligand). Dendritic cell activation leads to T-cell activation, in particular via expression of costimulatory molecules (B7, CD40), chemokines receptors (CCR-7), and cytokines (IL-12) (31).

A major role for dendritic cells has been established in lupus. Dendritic cell dysfunction may account for the loss of peripheral tolerance that characterizes lupus. Peripheral blood CD14+ monocytes from lupus patients, but not from normal controls, may act as mature dendritic cells that activate potentially autoreactive T cells. Maturation of these CD14+ cells is induced by elevated circulating levels of interferon-a (INFa) produced by a population of dendritic cells that infiltrate lupus lesions. These crucial pieces of evidence suggest that INFa and dendritic cells may represent therapeutic targets in patients with lupus (32,33).

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