title: C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy.
abstract: BACKGROUND
  Guillain-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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK. Rhona.mcgonigal@glasgow.ac.uk.
authors.forename: Rhona
authors.initials: R
authors.lastname: McGonigal
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Cunningham
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
authors.forename: Denggao
authors.initials: D
authors.lastname: Yao
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Barrie
authors.affiliation: Annexon Biosciences, 280 Utah Ave, Suite 110, South San Francisco, CA, 94080, USA.
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Fewou
authors.affiliation: College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Annexon Biosciences, 280 Utah Ave, Suite 110, South San Francisco, CA, 94080, USA.
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Willison
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism*; D003171:Complement Pathway, Classical / Q000235:genetics / Q000502:physiology*; D003964:Diaphragm / Q000378:metabolism / Q000473:pathology; D029382:Dicarboxylic Acid Transporters / Q000235:genetics; D004195:Disease Models, Animal; D005732:Gangliosides / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D020275:Guillain-Barre Syndrome / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017254:Leukemic Infiltration; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000378:metabolism; D012119:Respiration / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity; D027981:Symporters / Q000235:genetics; D013990:Tidal Volume / Q000187:drug effects / Q000235:genetics
chemical_list: D000906:Antibodies; D029382:Dicarboxylic Acid Transporters; D005732:Gangliosides; D011978:Receptors, Nicotinic; C487219:Slc13a5 protein, mouse; D027981:Symporters; D015922:Complement C1q