Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes

Abstract

Antiphospholipid antibodies (aPL) are associated with neurological diseases such as stroke, migraine, epilepsy and dementia and are thus associated with both vascular and non-vascular neurological disease. We have therefore examined the possibility that these antibodies interact directly with neuronal tissue by studying the electrophysiological effects of aPL on a brain synaptosoneurosome preparation. IgG from patients with high levels of aPL and neurological involvement was purified by protein-G affinity chromatography as was control IgG pooled from ten sera with low levels of aPL. Synaptoneurosomes were purified from perfused rat brain stem. IgG from the patient with the highest level of aPL at a concentration equivalent to 1:5 serum dilution caused significant depolarization of the synaptoneurosomes as determined by accumulation of the lipophylic cation [3H]-tetraphenylphosphonium. IgG from this patient as well as IgG from two elderly patients with high levels of aPL were subsequently shown to permeabilize the synaptosomes to labeled nicotinamide adenine dinucleotide (NAD) and pertussis toxin-ADP-ribose transferase (PTX-A protein) as assayed by labeled ADP-ribosylation of G-proteins in the membranes. No such effects were seen with the control IgG. aPL may thus have the potential to disrupt neuronal function by direct action on nerve terminals. These results may explain some of the non-thromboembolic CNS manifestations of the antiphospholipid syndrome.

Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: Results from an international inception cohort study

“…The most direct evidence supporting the hypothesis of autoantibody involvement in NPSLE is derived from studies of animal models (13)(14)(15)(16)(17), whereas evidence from human studies is frequently conflicting or inconclusive (18)(19)(20)(21)(22). This may be due in part to methodologic difficulties involving, for example, selection of patients for study, lack of rigor in the characterization of NP events, and differences between laboratories in assay techniques.…”

“…The latter include antiphospholipid antibodies (aPL), antiribosomal P antibodies (anti-P), and autoantibodies that bind to neuronal antigens such as the recently described antibodies to the NR2 glutamate receptor (13). Although there is biologic plausibility and data from in vitro studies and animal studies to implicate these autoantibodies in the causality of nervous system disease (13)(14)(15)(16)(17), studies of humans with SLE have yielded inconsistent findings (18)(19)(20)(21)(22). Previous investigations have been limited by their cross-sectional study design, heterogeneity of study patients in terms of disease duration, and lack of standardization in both the classification of NP events and the methodology used for autoantibody detection.…”

Antiphospholipid Antibodies Bind ATP: A putative Mechanism for the Pathogenesis of Neuronal Dysfunction

“…aPL IgG have been shown to bind to brain vascular endothelium, platelet membranes, neuronal membranes and myelin sheaths, and may consequently alter neural structure and function directly or indirectly (Del Papa et al 1995, Fanelli et al 1997. Permeabilization of synaptic structures by direct binding of aPL has recently been proposed as a pathogenetic mechanism in APS (Chapman et al 1999). This may be relevant since several neurological manifestations cannot be explained as consequences of vascular damage.…”

Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity

“…The main pathogenetic mechanism is vasculopathy and thrombosis, mediated by endothelial, platelet, and complement activation. A direct interaction between antiphospholipid antibodies and neuronal membrane antigens has also been demonstrated and may play a role in some APS-related manifestations such as seizures and chorea [21,45,48]. Anticoagulation is the main treatment in these patients, according to the recent recommendations for antiphospholipid positive patients (nongraded, owing to lack of consensus) [49,50], while antiplatelet agents are also administered as secondary prevention for thrombosis.…”