C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy

Abstract

IntroductionGuillain-Barré syndrome (GBS) is an autoimmune disease that results in acute paralysis through inflammatory attack on peripheral nerves, and currently has limited, non-specific treatment options. The pathogenesis of the acute motor axonal neuropathy (AMAN) variant is mediated by complement-fixing anti-ganglioside antibodies that directly bind and injure the axon at sites of vulnerability such as nodes of Ranvier and nerve terminals. Consequently, the complement cascade is an attractive target to reduce disease severity. Recently, C5 complement component inhibitors that block the formation of the membrane attack complex and subsequent downstream injury have been shown to be efficacious in an in vivo anti-GQ1b antibody-mediated mouse model of the GBS variant Miller Fisher syndrome (MFS). However, since gangliosides are widely expressed in neurons and glial cells, injury in this model was not targeted exclusively to the axon and there are currently no pure mouse models for AMAN. Additionally, C5 inhibition does not prevent the production of early complement fragments such as C3a and C3b that can be deleterious via their known role in immune cell and macrophage recruitment to sites of neuronal damage.Results and ConclusionsIn this study, we first developed a new in vivo transgenic mouse model of AMAN using mice that express complex gangliosides exclusively in neurons, thereby enabling specific targeting of axons with anti-ganglioside antibodies. Secondly, we have evaluated the efficacy of a novel anti-C1q antibody (M1) that blocks initiation of the classical complement cascade, in both the newly developed anti-GM1 antibody-mediated AMAN model and our established MFS model in vivo. Anti-C1q monoclonal antibody treatment attenuated complement cascade activation and deposition, reduced immune cell recruitment and axonal injury, in both mouse models of GBS, along with improvement in respiratory function. These results demonstrate that neutralising C1q function attenuates injury with a consequent neuroprotective effect in acute GBS models and promises to be a useful new target for human therapy.

Complement in the pathogenesis of Alzheimer’s disease

“…Annexon Biosciences ( http://www.annexonbio.com/science/ ) have developed C1q-blocking monoclonal antibodies (ANX005/007) for therapy of AD but have not yet addressed the delivery problem. Another anti-C1q antibody was neuroprotective in a mouse peripheral neuropathy model [ 90 ]. Numerous small-molecule anti-complement drugs targeting complement receptors (for example, C5a receptor antagonist peptides; [ 91 ]) or complement enzymes (for example, factor D blockers; [ 92 ]) are in development and approaching the clinic; however, to date, none have been designed with BBB penetrance in mind.…”

TREM2, Microglia, and Neurodegenerative Diseases

“…shown to be impaired in neurodegenerative conditions where microglia can be dysfunctional and/or excessive synaptic pruning might take place [23][24][25][26][27]. To visualize microglial activation in vivo[ 5 9 8 _ T D $ D I F F ] , positron emission tomography (PET) imaging has been employed in human AD studies [28][29][30][31].…”

Guillain–Barré syndrome: a century of progress

“…In summary, many collaborative efforts have demonstrated that anti-GM1 and anti-GQ1b antibodies bind to peripheral nerve and neuromuscular junctions 64,65 , and anti-GD1a antibodies bind to the nodes of Ranvier, paranodal myelin and neuromuscular junction 66,67,68 . Upon binding, the antibodies activate the complement cascade, resulting in formation of the membrane attack complex, disruption of sodium channel clusters at the node of Ranvier with disruption of nodal architecture 69 , and calcium influx and calpain-dependent neuronal and glial injury at the neuromuscular junction 70,71 .This injury can be ameliorated with complement inhibitors 72,73 .…”