Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-c and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis.

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

“…Increased necrosis rates could play a central role in enhanced inflammatory responses in SLE [18]. Necrotic cell death stimulates macrophages [19] and dendritic cells [20] and leads to inflammation [15,18,21] and development of murine SLE [22]. We proposed that increased release of necrotic materials from T cells would activate macrophages and dendritic cells (DCs) and enhance their capacity to produce NO and IFN-α̣ in SLE [18].…”

“…We proposed that increased release of necrotic materials from T cells would activate macrophages and dendritic cells (DCs) and enhance their capacity to produce NO and IFN-α̣ in SLE [18]. Indeed, DCs exposed to necrotic, but not apoptotic, cells induce lupus like-disease in MRL mice and accelerate the disease of MRL/lpr mice [22]. These data suggest that principal mitochondrial functions are involved in T cell activation.…”

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

“…We have shown previously that IFN-c is a critical cytokine involved in lupus pathogenesis [40]. The imbalanced IL-2 versus IFN-c production therefore also reflects the dysregulated Teff functions.…”

“…We have also shown subsequently in vivo evidence demonstrating the therapeutic benefit of IL-2 treatment in the MRL/lpr mice by using attenuated Salmonella typhimurium as the gene carrier [39]. Since IL-2 is an essential growth factor for Treg differentiation and proliferation, we next examined the ability of MRL/lpr Teff to produce IL-2 and IFN-c, two Th1 cytokines known to be differentially implicated in lupus pathogenesis [5,40]. To exclude the possibility that the defective IL-2 secretion was a cell dilution effect due to the presence of a large number of abnormal CD4 -CD8 -double-negative T cells [11], purified Teff were used for the study.…”

Interaction between antigen presenting cells and autoreactive T cells derived from BXSB mice with murine lupus

“…Intravenous injection of BM-derived DCs pulsed with U1 snRNP-A protein into BALB/c and DBA-2×NZW F1 (H-2 d/u ) mice elicited autoreactive T cell and IgG anti-U1A responses [29]. Chronic maturation of tissue DCs could induce severe organ-specific autoimmune disease and systemic autoimmunity [30][31][32]. In addition, transfer of DCs, isolated from donors with acute autoimmune disease or propagated in vitro under conditions that induce maturation, generates a strong Th-1 response and eventually leads to autoimmune disease such as EAE and diabetes in mice [33][34].…”