Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensive in vitro and in vivo studies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.

Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE), causing morbidity and mortality in 40-60% of SLE patients. The pathogenic mechanisms of LN are not completely understood. Recent studies have demonstrated the presence of various immune cell populations in lupus nephritic kidneys of both SLE patients and lupus-prone mice. These cells may play important pathogenic or regulatory roles in situ to promote or sustain LN. Here, using lupus-prone mouse models, we showed the pathogenic role of a kidney-infiltrating CD11c myeloid cell population in LN. These CD11c cells accumulated in the kidneys of lupus-prone mice as LN progressed. Surface markers of this population suggest their dendritic cell identity and differentiation from lymphocyte antigen 6 complex (Ly6C) mature monocytes. The cytokine/chemokine profile of these renal-infiltrating CD11c cells suggests their roles in promoting LN, which was confirmed further in a loss-of-function in-vivo study by using an antibody-drug conjugate (ADC) strategy targeting CX CR1, a chemokine receptor expressed highly on these CD11c cells. However, CX CR1 was dispensable for the homing of CD11c cells into lupus nephritic kidneys. Finally, we found that these CD11c cells co-localized with infiltrating T cells in the kidney. Using an ex- vivo co-culture system, we showed that renal-infiltrating CD11c cells promoted the survival, proliferation and interferon-γ production of renal-infiltrating CD4 T cells, suggesting a T cell-dependent mechanism by which these CD11c cells promote LN. Together, our results identify a pathogenic kidney-infiltrating CD11c cell population promoting LN progression, which could be a new therapeutic target for the treatment of LN.

Plasmacytoid dendritic cells (pDCs) are professional type I IFN producers believed to promote lupus. However, questions exist about whether they function at the same level throughout the course of lupus disease. We analyzed high-purity pDCs sorted from lupus mice. Although pDCs produced a large amount of IFN-α during disease initiation, those sorted from late-stage lupus mice were found to be defective in producing IFN-α. These pDCs expressed an increased level of MHC, suggesting a functional drift to Ag presentation. We examined the potential mechanism behind the defect and identified a novel transcriptional factor, Foxj2, which repressed the expression of several genes in pDCs, but not IFN-α. Dysregulation in pDCs appears to be predisposed, because they exhibited an altered transcriptional profile before the onset of clinical signs. Our results suggest that pDCs do not function the same throughout the disease course and lose the ability to produce IFN-α in late-stage lupus mice.