Figure 2. TLR activation pathway in plasmacytoid dendritic cells and its regulation in health and disease.

PDC selectively express TLR7 and TLR9, which are expressed in the endosomal compartment. TLR activation is mediated by engagement of viral single strand RNA and bacterial DNA, respectively (non self-recognition). Self-nucleic acids, in complex with the small cationic antimicrobial peptide LL-37 are able to trigger TLR7/9 in pDC. Entry of self-DNA/LL-37 complexes can also be facilitated by plasma cell-derived autoantibodies that engage FcγRIIA. In addition, TLR7 can be activated by synthetic compounds such as Imiquimod or R848, while TLR9 recognizes synthetic CpG oligodeoxynucleotides, including CpG-A and CpG-B. TLR7/9 triggering leads to activation of the myeloid primary-response gene 88 (MyD88) and downstream signaling cascade via NFκB pathway, IRF5/7, and MAPK. This ultimately lead to expression of type I/III IFN, pro-inflammatory cytokines IL6 and TNFα, and costimulatory molecules, such as CD40, CD80, and CD86, that are the key components of pDC-derived antiviral response and antigen presentation. In addition pDC can exert cytotoxic properties via expression of TRAIL, and Granzyme B, which is also involved in the tolerogenic properties of pDC within tumor environment. On the right are listed the different functions of pDC and the different regulators that separate the physiological aspects from the dysfunctional pDC-derived pathophysiology. Antiviral response is mainly controlled via miRNA regulations (miR-146a, miR-155/miR-155*) and failure to do so can lead to autoimmune diseases such as SLE, Sjögren’s syndrome, and psoriasis.