Altered dendritic cells with tolerizing phenotype in patients with systemic lupus erythematosus

Abstract

Earlier we showed the generation of tolerizing human monocyte-derived DC following interaction with iC3b-opsonized apoptotic cells. In this study we examine the generation of DC with our previously described tolerogenic phenotype in patients with the systemic autoimmune disease systemic lupus erythematosus (SLE). Monocyte-derived DC were generated in 71 SLE patients, characterized, and then tested for clearance of iC3b-opsonized 1,1 0 -dioctadecyl-3,3,3 0 ,3 0 -tetramethyl-indocarbocyanineperchlorate-stained apoptotic cells using flow cytometry, and for autologous T-cell activation using autologous mixed lymphocyte reaction (AMLR), at the same time as controls. Compared with healthy, ageand gender-matched controls, SLE patients showed upregulation of MHC class II, with a mean expression of 130.5%736.8% (po0.007); CD86 in immature DC from SLE patients, generated in autologous human or control plasma, were also upregulated, with mean expression 106.6%718.0% (po0.03). A significant (420%) reduction in iC3b-apoptotic cell uptake, together with increased autologous mixed lymphocyte reaction, was seen in 75% of SLE patients. Mean 1,1 0 -dioctadecyl-3,3,3 0 ,3 0 -tetramethyl-indocarbocyanineperchloratestained apoptotic cell acquisition was 70.0%724% (po0.0001) compared with healthy controls. Altered generation of a tolerizing DC phenotype was seen in at least one third of SLE patients following interaction with iC3b-opsonized apoptotic cells. These results suggest that a substantial portion of SLE patients fail to generate DC with a tolerizing phenotype.

Caspase-8 Acts as a Molecular Rheostat To Limit RIPK1- and MyD88-Mediated Dendritic Cell Activation

“…Increased numbers of the other major DC subtype, plasmacytoid DCs, are seen in peripheral tissues of SLE patients (49). Furthermore, DCs from SLE patients fail to yield a tolerizing phenotype under experimental conditions (50) and produce high levels of proinflammatory IL-6, which is known to inhibit CD4 + CD25 + regulatory T-cells (51). These findings are recapitulated in DCs from mice with SLE-like disease in which the number of DCs is increased as is their secretion of pro-inflammatory cytokines (IL-12 and IL-6), cell-surface activation and maturation markers, induction of T-cell effector responses, and reduction of regulatory T-cell function compared to control DCs (52).…”

Phenotypic and functional abnormalities of bone marrow-derived dendritic cells in systemic lupus erythematosus

“…Central to these changes are believed to be altered functions of DCs, the most important APCs [3,4,14,23-25]. …”

“…Dendritic cells (DCs), the most effective antigen-presenting cells (APCs), are capable of activating naïve T cells and initiating T-cell responses. DCs have been hypothesized to play an important role in the pathogenesis of SLE [3,4]. …”

“…In SLE, abnormalities in peripheral blood-isolated DCs, monocyte-derived DCs, and mouse BM-derived DCs have been reported [3,7,8,13,14]. All of these studies have indicated a crucial role of DCs in the pathogenesis of SLE through either a deficiency in sustaining peripheral tolerance to self-Ag or an increased susceptibility to infection.…”

Dendritic cell function in lupus: Independent contributors or victims of aberrant immune regulation

“…Blood SLE monocytes display DC-like functions as they capture antigens and autoantigens and present them to CD4 þ and CD8 þ T-cells [40]. A substantial portion of SLE patients fails to generate DCs with a tolerizing phenotype [41,42]. The cAMP response element modulator (CREM)a is a transcriptional repressor contributing to abnormal T-cell function in SLE [43,44].…”