Induction by Lupus Immune Complexes Differentially Regulate Inflammatory Gene Plasmacytoid Dendritic Cells and C1q

Immune complexes (ICs) play a pivotal role in causing inflammation in systemic lupus erythematosus (SLE). Yet, it remains unclear what the dominant blood cell type(s) and inflammation-related gene programs stimulated by lupus ICs are. To address these questions , we exposed normal human PBMCs or CD14 + isolated monocytes to SLE ICs in the presence or absence of C1q and performed microarray analysis and other tests for cell activation. By microarray analysis, we identified genes and pathways regulated by SLE ICs that are both type I IFN dependent and independent. We also found that C1q-containing ICs markedly reduced expression of the majority of IFN-response genes and also influenced the expression of multiple other genes induced by SLE ICs. Surprisingly, IC activation of isolated CD14 + monocytes did not upregulate CD40 and CD86 and only modestly stimulated inflammatory gene expression. However, when monocyte subsets were purified and analyzed separately, the low-abundance CD14 dim (" patrolling ") subpopulation was more responsive to ICs. These observations demonstrate the importance of plasmacytoid dendritic cells, CD14 dim monocytes, and C1q as key regulators of inflammatory properties of ICs and identify many pathways through which they act. S ystemic lupus erythematosus (SLE) is a multisystem au-toimmune disease characterized by the presence of high titer autoantibodies directed against self nucleoproteins (reviewed in Ref. 1). Some of these Abs interact with Ags to form immune complexes (ICs) that deposit in the kidneys, skin, and vas-culature (2, 3). ICs also directly engage FcgRs expressed on mac-rophages and neutrophils, resulting in the release of proinflammatory cytokines, proteolytic enzymes, and reactive oxygen intermediates (4). Thus, ICs, especially after complement activation, are thought to be the predominant inducers of tissue injury in SLE (3, 5). Despite these findings, individuals with loss-of-function mutations of the first complement component, C1q, almost invariably develop SLE (reviewed in Ref. 6). This " lupus paradox " (7), in which complement activation promotes tissue injury, yet complement deficiency predisposes to SLE, has, in part, been reconciled by studies demonstrating the protective role of classical complement pathway components (C1-4) in facilitating the clearance of lupus Ags (apoptotic debris) (8–10). In contrast, it is the complement components downstream of C3, especially release of C3a and C5a that promote chemotaxis and inflammation as well as deposition of C5b-9 together, that promote tissue injury (11–13). More recently, C1q has been shown to protect against SLE by a separate effect, via preventing the …