Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin‐17

Abstract

Objective. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of antinuclear autoantibodies. Increased apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE, but the underlying mechanisms remain elusive. During apoptosis apoptotic blebs are formed in which autoantigens are clustered. The cellular remnants after blebbing are referred to as apoptotic cell bodies. We undertook this study to compare the effects of apoptotic blebs and apoptotic cell bodies on maturation of dendritic cells (DCs) and their T cell stimulatory capacity in a murine setting.Methods. The uptake by DCs of apoptotic blebs and apoptotic cell bodies was analyzed by flow cytometry and confocal microscopy. DC maturation and DCinduced T cell activation were determined by measuring expression of costimulatory molecules using flow cytometry and by measuring production of cytokines using enzyme-linked immunosorbent assay.Results. DCs internalized apoptotic blebs more efficiently than apoptotic cell bodies. Incubation of DCs with apoptotic blebs resulted in increased CD40 and CD86 expression and increased interleukin-6 (IL-6) and tumor necrosis factor ␣ production, while apoptotic cell bodies had no stimulatory effects. Using chloroquine, apoptotic bleb-induced DC maturation was shown to be independent of Toll-like receptors 3, 7, and 9. Interestingly, in cocultures with allogeneic T cells, bleb-matured DCs induced production of IL-2, interferon-␥, and, in particular, IL-17, suggesting a Th1/Th17 response.Conclusion. Apoptotic blebs, in contrast to apoptotic cell bodies, induce DC maturation, thereby providing DCs with increased Th17 cell stimulatory capacity. These data imply that apoptotic bleb-induced DC maturation represents an important driving force in the autoimmune response in SLE.

Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept

“…Thus, silencing of renal DNaseI expression may have immediate and harmful consequences linked to activation of the complement system by chromatin-IgG complexes (79). In addition, accumulated apoptotic chromatin fragments that are enriched in apoptosis-induced chromatin modifications (80)(81)(82) may affect cells of the innate immune system by triggering TLR7-9 and the Clec4e receptor. The apoptosis-induced chromatin modifications present in accumulated chromatin may be involved in sustained systemic autoimmune responses against chromatin ( [80][81][82].…”

Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

“…This in turn drives T cell activation and B cell maturation into autoantibody-producing B cells (4)(5)(6)(7)(8). Although it is well accepted that higher levels of circulating ACs can be due to decreased clearance of ACs in SLE and mouse models of lupus, the underlying mechanism for the clearance defect is not completely understood (2,(9)(10)(11). Marginal zone macrophages (MZMs) surrounding the splenic follicles have been reported to have the capability of both efficient clearance of ACs and induction of tolerance to AC-Ags (12)(13)(14)(15).…”

Effects of simvastatin on the function of dendritic cells in patients with rheumatic arthritis

“…On the one hand, they can promote the activation and proliferation of T lymphocytes and Th17 differentiation through up-regulation of MHC and co-stimulatory molecule CD86. On the other hand, they can mediate inflammatory responses through producing proinflammatory cytokines like IL-12 and TNF-alpha [17,18] . Therefore, DCs play a central role in orchestrating the immune response and inducing toleration of immune response against self and non-self antigens.…”