Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Abstract

Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented. AbbreviationsACA, anti-cardiolipin antibodiesx; Abbreviations, anti-nuclear antibodies; CSF, cerebrospinal fluid; FJB, Fluoro Jade B stain; NP-SLE, neuropsychiatric systemic lupus erythematosus; PBS, phosphate buffered saline

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

“…While the QNP-treated groups gained weight (from B42 g to B44 g) over 2 weeks, SAL-injected males showed comparable body weight (B40 g) at both time points (treatment by time: F(1,35) = 4.096, P = 0.05). As observed earlier, 13,32 brain mass was consistently lower in MRL-lpr than in MRL þ / þ mice (456710 vs 50876 mg; substrain: F(1,35) = 10.150, P < 0.01), and this was not significantly altered by the QNP treatment (47472 vs 51474 mg).…”

Neuroimmunopathology in a murine model of neuropsychiatric lupus

“…In the case of glutamate toxicity, anti-DNA antibodies may play an important role. These autoantibodies have recently been found to cross-react with central NMDA receptors in mice, producing neuronal apoptosis (DeGiorgio et al, 2001), and a similar IgG-mediated neurodegenerative event is proposed to occur in MRL-lpr brains (Sakic et al, 2005b). This causal relationship between NR2 receptor-reactive autoantibodies and brain damage has also been reported in NP-SLE patients (Omdal et al, 2005).…”

“…More specifically, the subventricular zone (Sakic et al, 2000b;Sidor et al, 2005), subgranual zone (Ballok et al, 2003, and substantia nigra (Ballok et al, 2004a), known to contain proliferative progenitor cells capable of neurogenesis (Yamashita et al, 2006;Suh et al, 2005;McGuire et al, 2001;Zhao et al, 2003), show signs of damage in these animals. CSF from diseased lupus mice is also cytotoxic to neurons and neuronal progenitor cells in vitro (Maric et al, 2001;Ballok et al, 2004a) supporting a link between toxic CSF IgG and neuronal/progenitor cell damage (Sidor et al, 2005;Sakic et al, 2005b). If in vitro findings are predictive of in vivo events, then autoimmune-induced lesions of germinal layers may reduce the developmental and regenerative capacity of MRL-lpr brains.…”

Disturbed distribution of proliferative brain cells during lupus-like disease

“…However, given that increased ventricle/brain area ratio, emergence of protuberances, and SGZ shrinkage occur mainly at the onset of autoimmune disease, this deficiency seems unlikely to account for these effects. Second, neuroinflammation is reported to disrupt neurogenesis ( More recently, we showed that cells from the C17.2 neural stem cell line and neurospheres from several mouse strains die when incubated with cerebrospinal fluid (CSF) from diseased MRL/lpr mice (Sakic et al, 2005b). Therefore, the pathogenic cascade in vivo may include drainage of circulating immune factors (e.g., activated cytotoxic lymphocytes, cytokines and/or autoantibodies) via breached blood-brain barrier into the CSF and diffusion into neighboring tissue, leading to subsequent detrimental effects on proliferative cells.…”