Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-a seems to be a key cytokine in SLE as an activated IFN-a system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-a. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-a. IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibodies against various nuclear antigens, as well as the generation of immune complexes (IC) leading to inflammatory responses in skin, kidneys, joints, the vasculature and the heart [1]. Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19]. Moreover, the administration of IFN-a for therapeutic purposes induces typical SLE autoantibodies as a side effect [20,21]. Both these phenomena are poorly understood and no unifying hypothesis, incorporating the role of complement deficiency and elevated IFN-a levels in the induction of SLE, exists. Recently, we described an unusual deposition of IgMcontaining immune complexes (IgM-IC) in the splenic marginal zone (MZ) of complement C4-deficient (C4 null ) mice. This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which i...

ITGAM coding variant (rs1143679) influences the risk of renal disease, discoid rash and immunological manifestations in patients with systemic lupus erythematosus with European ancestry

“…ITGAM (CD11b) expression was shown to increase DNA fragmentation, a prerequisite for apoptosis, and the level of fragmented DNA is increased in intravascular cells, which induces interferon α in SLE mice 9. CD11b also induces tumour necrosis factor α10 and modulates the innate immune mechanism11 in patients with SLE.…”

The Role of Extracellular DNA in Autoimmunity in SLE

“…Indeed, the binding of complement to apoptotic and necrotic cells can lead to opsonization and phagocytosis by macrophages, which can also affect the amounts of DNA that can enter the circulation. These proteins may also bind directly to DNA and therefore modulate its extracellular trafficking [30–38]. Among these humoral factors, complement appears to play an important role in determining disease susceptibility as exemplified by the development of lupus in humans with hereditary deficiency of C1q and C4 as well as the corresponding murine models.…”

B cell tolerance to epidermal ribonuclear-associated neo-autoantigenin vivo

“…This could be a result of presentation of their cognate antigen in a tolerogenic environment, as it has been found that DCs induce immunity or tolerance depending solely upon their activation status . However, in the present study this explanation appears unlikely, given the established general proinflammatory environment in 564Igi mice , C4‐deficient mice , and 564Igi C4‐deficient mice in particular . Consequently, we speculate that it is an active dominant‐negative tolerance mechanism, mediated probably by forkhead box protein 3 (FoxP3) + regulatory T cells (T regs ).…”