Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases

The mammalian innate immune system seems to have developed three distinct systems to sense viral infection through the recognition of nucleic acids. These are the endosomal Toll-like receptor 7 (TLR7)/TLR8/TLR9 signalling pathway through MyD88 (myeloid differentiation primary-response gene 88), the endosomal TLR3 signalling pathway through TRIF (Toll/interleukin-1 (IL-1) receptor-domain-containing adaptor protein inducing interferon-β) and the cytosolic RIG-I (retinoic-acid-inducible gene I) signalling pathway.The endosomal TLR7/TLR9–MyD88 pathway is exclusively used by plasmacytoid dendritic cells (pDCs). pDCs use neither the endosomal TLR8–MyD88 pathway nor the TLR3–TRIF pathway, which are instead mainly used by myeloid cells, such as myeloid DCs, to detect viral RNA. In addition, pDCs do not use the cytosolic RIG-I pathway, which is widely used by myeloid cells and all non-haematopoietic cells to detect viral double-stranded RNA.pDCs seem to detect A-type CpG-containing DNA in the early endosomes through TLR9 that is coupled to interferon-regulatory factor 7 (IRF7) activation and leads to type I interferon (IFN) production. By contrast, pDCs sense B-type CpG-containing DNA in the late endosomes through TLR9 that is coupled to nuclear factor-κB (NF-κB) activation and leads to tumour-necrosis factor and IL-6 production, as well as to the maturation of the pDCs into mature antigen-presenting cells.Several host factors, including DNA-specific antibodies, the antimicrobial peptide LL37, the nuclear DNA-binding protein HMGB1 (high-mobility group box 1 protein) or small ribonucleoprotein, allow self DNA or self RNA to activate both autoreactive B cells and pDCs through endosomal TLR9 or TLR7, leading to the development of autoimmune diseases, such as systemic lupus erythematosus and psoriasis.pDCs may detect self DNA and self RNA frequently and mount low level of type I IFN responses when cell death occurs in normal tissues during tissue renewal, stress and repair processes.This unwanted pDC response is potentially under tight control by rapid clearance of dying cells by macrophages; by degradation of self DNA and self RNA by DNases and RNases, respectively; by compartmentalization of TLR7 and TLR9 within the endosomes; and by receptor-mediated negative regulation of TLR7- or TLR9-induced IFN responses in pDCs.