Immune mechanisms, the role of complement, and related therapies in autoimmune neuropathies

ABSTRACT

Introduction

Autoimmune neuropathies have diverse presentations and underlying immune mechanisms. Demonstration of efficacy of therapeutic agents that inhibit the complement cascade would confirm the role of complement activation.

Areas covered

A review of the pathophysiology of the autoimmune neuropathies, to identify those that are likely to be complement mediated.

Expert Opinion

Complement mediated mechanisms are implicated in the acute and chronic neuropathies associated with IgG or IgM antibodies that target the Myelin Associated Glycoprotein (MAG) or gangliosides in the peripheral nerves. Antibody and complement mechanisms are also suspected in the Guillain-Barré syndrome and chronic inflammatory demyelinating neuropathy, given the therapeutic response to plasmapheresis or intravenous immunoglobulins, even in the absence of an identifiable target antigen. Complement is unlikely to play a role in paraneoplastic sensory neuropathy associated with antibodies to HU/ANNA-1 given its intracellular localization. In chronic demyelinating neuropathy with anti-nodal/paranodal CNTN1, NFS-155, and CASPR1 antibodies, myotonia with anti-VGKC LGI1 or CASPR2 antibodies, or autoimmune autonomic neuropathy with anti-gAChR antibodies, the response to complement inhibitory agents would depend on the extent to which the antibodies exert their effects through complement dependent or independent mechanisms. Complement is also likely to play a role in Sjogren’s, vasculitic, and cryoglobulinemic neuropathies.

KEYWORDS:

• Anti-ganglioside antibodies
• autoimmune neuropathy
• autonomic neuropathy
• chronic inflammatory demyelinating polyneuropathy
• complement activation
• Guillain-Barre syndrome
• multifocal motor neuropathy
• myelin associated glycoprotein
• paraneoplastic neuropathy
• vasculitic neuropathy

Article highlights

• Autoimmune neuropathies have diverse presentations and underlying immune mechanisms

• Neuropathy syndromes associated with autoantibody activity include: acute motor axonal neuropathy (AMAN) with IgG anti-GM1 or GD1a ganglioside antibodies, acute ataxic neuropathy with ophthalmoplegia (Miller-Fisher syndrome) that is associated with IgG anti-GQ1b ganglioside antibodies, acute pharyngeal-cervical-brachial neuropathy associated with anti-GT1a ganglioside antibodies, chronic demyelinating neuropathy associated with IgM anti-MAG antibodies, multifocal motor neuropathy (MMN) with IgM anti-GM1 ganglioside antibodies, chronic demyelinating neuropathy associated with IgG anti-nodal/paranodal antibodies to CNTN1, NFS-155 or CASPR1, chronic ataxic neuropathy associated with IgM anti-GD1b and disialylated ganglioside antibodies, autoimmune autonomic ganglionopathy associated with anti-ganglionic acetylcholine receptor (gAChR) antibodies, paraneoplastic sensory neuropathy associated with IgG anti-HU/ANNA antibodies, and neuromyotonia associated with anti-voltage gated potassium (VGKC) LGI1 or CASPR2 antibodies.

• Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) and chronic inflammatory demyelinating neuropathy (CIDP) are suspected to be antibody and complement dependent, given their response to treatment with plasmapheresis or IVIG, even in the absence of an identified target antigen.

• Autoantibodies can cause neuropathy by complement dependent or independent mechanisms. IgG4 subclass, non complement fixing antibodies can disrupt cell surface and receptor interactions. Those that are IgM, IgG1 or IgG3, can in addition activate complement. The complement cascade can also be spontaneously activated as a consequence of dysregulation or deficiencies in complement inhibitory proteins.

• In most patients with chronic demyelinating neuropathy with anti-noda/paranodal antibodies and in a subset of patients with myotonia and anti-LGI1 or CASPR2 antibodies, the antibodies are of the IgG4 subtype that does not activate complement, in which case the neuropathy is likely to be mediated by complement independent mechanisms. Complement is also unlikely to play a role in the paraneoplastic sensory neuropathy associated with antibodies to HU/ANNA-1 which is an intracellular antigen.

• Complement activation is also likely to play a role in vasculitic, cyroblobulinemic and Sjogren’s neuropathies. Avacopan, an oral C5a inhibitor, has recently been FDA approved for treatment of ANCA associated vasculitis.

• Response to treatments that inhibit complement activation would depend on the extent to which the antibodies exert their effects through complement dependent or independent mechanisms. Confirmation of complement mediated mechanisms, and the efficacy of anti-complement therapies would require proof in controlled clinical trials of agents that inhibit the complement cascade.

Declaration of Interests

Norman Latov is the PI of a grant to Weill Cornell Medicine by Takeda, and has served as consultant to Therapath Partners, Polyneuron, Apellis, and Takeda. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper is not funded.