Lack of Chromatin and Nuclear Fragmentation In Vivo Impairs the Production of Lupus Anti-Nuclear Antibodies

Abstract

Nuclear autoantigens in systemic lupus erythematosus are thought to derive primarily from apoptotic cells, yet there is no direct evidence that interfering with apoptosis impairs the generation of lupus autoantibodies. Here we use a mouse model that lacks the endonuclease caspase-activated DNase (CAD), resulting in an absence of chromatin and nuclear fragmentation during apoptotic cell death. We show that in this mouse, production and release into circulation of chromatin is impaired after exposure to several apoptotic triggers, but that the absence of CAD does not interfere with upstream steps of apoptosis or immune system function. Finally we show that in CAD-mutant mice, impaired lupus autoimmunity is skewed toward known cytoplasmic components, and autoimmunity toward membrane autoantigens is preserved, while autoimmunity toward chromatin and other lupus nuclear targets is severely impaired or absent. We also show, as control, that the induction of experimental autoimmune encephalomyelitis is not affected by the absence of CAD. Thus, our work in vivo strongly suggests that apoptotic molecular steps during cell death generate nuclear autoantigens to sustain the specific autoimmune response in systemic lupus erythematosus.

Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e

“…For example, similar in situ exposure and retention of large un-fragmented chromatin fragments have been described in several experimental nuclease deficiencies on non-autoimmune backgrounds (see e.g. [9], [59]–[61]). The clinical consequence of chromatin fragments in these experimental nuclease deficiencies differ from that in kidneys of individuals with lupus nephritis, simply because in the latter, antibodies to chromatin are present.…”

Roles of the Major Apoptotic Nuclease-DNA Fragmentation Factor-in Biology and Disease

“…In addition, DFF null mice do not develop SLE. By contrast however, in a pristine-induced animal model for SLE, DFF null mice produce significantly lower levels of antibodies to chromatin, small nuclear ribonucleoprotein particles and to other nuclear components, when compared to control wild type mice, but produce normal levels of autoantibodies to cytoplasmic components [105]. It can be concluded from these results that DFF may contribute to the susceptibility to acquire SLE.…”

“…[20]. Furthermore, when DFF null mice are challenged with specific antigens, they mount a normal immune response [105]. In addition, DFF null mice do not develop SLE.…”

Dying cell clearance and its impact on the outcome of tumor radiotherapy

“…Coligation of additional receptors for DAMPs instead appears to be required. Research in the field of autoimmunity has convincingly shown that dying cell-derived nucleosomal material is very potent in this regard (Frisoni et al, 2007; Urbonaviciute et al, 2008). Hence, interfering with DNase II activity, which in phagocytes mediates the proper degradation of engulfed prey cell DNA, could represent a promising strategy to stimulate the described IFN cascade required for the induction of productive immune responses and well-known for its crucial role in the etiopathogenesis of autoimmune diseases, such as SLE (Kawane et al, 2006; Marshak-Rothstein, 2006; Deng and Tsao, 2010).…”