Plasmacytoid dendritic cells in systemic and cutaneous lupus erythematosus: an evolving understanding

Lupus erythematosus is a chronic, heterogenous autoimmune disease driven by a complex interplay of genetic, environmental and hormonal factors, which can manifest as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), or both simultaneously. Plasmacytoid dendritic cells (pDCs) are thought to play a central role in disease pathogenesis following the dysregulated and sustained production of type I interferon (IFN-I), leading to widespread immune system activation and chronic inflammation, resulting in organ and tissue damage characteristic of lupus. While treatment of lupus has shown success with approaches that inhibit the IFN pathway/IFN-I production, targeting pDCs is of great interest due to their accumulation in lesional tissues and key role in IFN-I production. However, SLE and CLE pathogenesis is clouded by unknowns including limited understanding of the pathophysiological loss of IFN pathway negative feedback, the complexity of IFN production by non-pDC cells (including pDC plasticity and role of different subsets/states), the role of other cytokines and chemokines in disease pathogenesis, and differences in pDC activation and downstream effects in SLE and CLE. Conceivably, different IFN-I-producing cells may be important in different organs, patients, and disease stages. As understanding of the role of pDCs in IFN-I production evolves, there is great potential to develop more targeted and effective treatments that can enhance patient outcomes to ensure pathophysiological and chronic inflammation is negated while maintaining physiological immunity to infection.