Abstract Dendritic cells (DCs) are professional antigen presenting cells displaying the unique capability to activate naïve T cells. DCs react to pathogen encounter also by the production of mediators of inflammation, including pro-inflammatory cytokines. Because of this complex role, any imbalance in DC function reflects into defective or exaggerated immune response and tissue damage. DCs comprise two main subsets, namely conventional or classical DCs (cDCs), that are dedicated antigen presenting cells, and plasmacytoid DCs (pDCs), that respond to nucleic acids by releasing high amounts of type I interferons (IFNs). Since the formal demonstration that DC can prime autoreactive naïve T cells, a full body of evidence has implicated DCs in virtually all manifestations of autoimmunity, although their exact pathogenic role often remains poorly characterized. The recent availability of progressively more refined strategies of constitutive and inducible DC ablation is contributing in defining the precise role of DCs at least in some autoimmune disease models. This review aims at critically summarizing the current literature concerning selected aspects of DC biology that, when altered, facilitate autoimmunity. These aspects include: i) mechanisms of tissue entry and accumulation, ii) mechanisms of activation and iii) orchestration of the immune balance by cytokine production. A special focus will be on inappropriate DC activation by signals released by damaged tissues via innate immune receptors, such as Toll-like receptors. These signals are responsible, in pDCs, for exaggerated type I IFN production, the hallmark of a set of apparently distant autoimmune conditions such as systemic lupus erythematosus and type 1 diabetes; whereas in cDCs, they trigger DC rapid maturation and Th1/Th17 cytokine secretion. Tissue-derived molecules also contribute to further promote tissue damage and autoantigen spreading, possibly through pDC-derived Granzyme B secretion. Finally, the therapeutic possibilities based on DC targeting in human autoimmune diseases will be briefly summarized. Highlights Dendritic cells are key regulators of immune responses. Their altered activation is involved in the onset autoimmunity. Trafficking of conventional and plasmacytoid dendritic cells plays a crucial role in the pathogenesis of autoimmune diseases. Dendritic cell targeting represents a new promising strategy in the therapy of human autoimmune diseases.
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