Background/Purpose: Dendritic cells (DCs) activate the immune system with a variety of cytokines and co-stimulatory molecules. Our group recently described the Notch ligand Delta-like Ligand 4 (DLL4) on human DCs and discovered that DLL4+ DCs were critical in regulating Th1 and Th17 differentiation. Due to the association of DCs, Th17 and activity with SLE, the goal of this work was to evaluate DLL4 expression in human SLE DCs.

Methods: Peripheral blood from healthy controls and patients with SLE were collected after obtaining informed consent. A total of 11 SLE patients and 13 sex and aged matched control were investigated. A multicolor flow cytometric analysis using a BD LSRII flow cytometer was used to identify DCs. DLL4 expression was determined by surface staining of CD1c⁺ DCs and pDCs. DCs were analyzed either in PBS or in the presence of the Toll-like Receptor (TLR) 7 agonist R848. Lupus activity was measured by SLE disease activity index (SLEDAI) and values were extracted from EPIC, the Temple University Hospital’s Electronic Medical Record system. Statistical analysis was performed with JMP^® Software. Student’s t-test, ANOVA, MANOVA, and least squares regression were used with a p < 0.05 was considered to be significant.

Results: We found that DLL4⁺ CD1c⁺ DCs in lupus patients at rest were 5-fold higher than in controls (p=0.002). Moreover, DLL4^– CD1c⁺ DCs were 2.1-fold higher in controls at rest (p=0.002). Interestingly also DLL4⁺ pDCs were 3.3-fold higher in lupus patients at rest (although not significant). After TLR7 stimulation, lupus patients had 3.3-fold more DLL4⁺ pDCs and those were 3.3-fold more responsive (p<0.001). We next correlated DLL4 expression and disease activity measured by SLEDAI. Interestingly SLEDAI score correlated with DLL4+ CD1c+ DCs after TLR7 stimulation. In lupus patients with no disease activity, DLL4⁺ pDCs were 3-fold more responsive to TLR7 triggering. Next we correlated DLL4+ DCs with SLE flares and found that DLL4⁺CD1c⁺ DCs were 2.3-fold more responsive to R848 (p=0.03) and 1.2-fold more responsive in a flare (not significant).

Conclusion: Our results suggest that DLL4+ DCs are a marker of chronic activation in SLE patients. Moreover, this particular group of DCs demonstrates propensity to activate upon TLR triggering, a major component of lupus pathogenesis. The SLEDAI scores and flares results findings are consistent. Finally DLL4⁺ pDCs could be a marker for SLE disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/notch-ligand-delta-like-ligand-4-dll4-expression-on-dendritic-cells-is-increased-in-systemic-lupus-erythematosus/