Anti-LGI4 antibody-positive autoimmune nodopathy: clinical features and pathomechanisms

Abstract

　We have discovered a novel autoantibody against leucine-rich repeat LGI family member 4 ( LGI4 ) localized at juxtaparanodes and satellite glia in the dorsal root ganglion in patients with chronic inflammatory demyelinating polyneuropathy ( CIDP ) by tissue-based indirect immunofluorescence assay using mouse sciatic nerves and dorsal root ganglia. We have developed a live cell-based assay for LGI4-IgG and found that 8/131 ( 6.1% ) CIDP patients were positive for LGI4-IgG. The dominant tissue-binding IgG subclasses were IgG4 in four patients, IgG1 in two patients, and IgG3 and IgG2 in one patient each. Patients had a relatively old onset age ( median 72 years ) . Four patients had acute/subacute onset and four had chronic onset. Six showed typical CIDP phenotype while two showed multifocal acquired demyelinating sensory and motor ( MADSAM ) neuropathy phenotype. Main symptoms/signs were motor weakness ( eight cases ) , muscle atrophy ( four ) , deep and superficial sensory impairment ( eight and seven, respectively ) , Romberg sign ( four ) , and finger and hand tremor ( five ) . CSF showed extremely high protein levels ( median 253 mg/dL ) . Three chronic cases had nerve hypertrophy. Intravenous immunoglobulin ( IVIg ) administration was partially effective in 7/7 patients. Notably, one patient with predominant LGI4-IgG1/2 and no LGI4-IgG4 showed a moderate reduction of myelinated fibers with endoneurial edema and numerous onion bulbs with numerous macrophage infiltration in the biopsied sural nerve. Schwann cell proliferation was significantly higher after incubation with LGI4-IgG than with HC-IgG in culture, and Krox20 mRNA levels were significantly lower with LGI4-IgG than with CIDP- or HC-IgG. With intraneural injection, both LGI4-IgG4 and -IgG1/2 deposited mainly at the nodes extending towards the paranodes and caused nodal/paranodal alterations. Anti-LGI4 antibody-positive autoimmune nodopathy shows acute monophasic and chronic progressive courses with nerve hypertrophy. LGI4-IgG may be pathogenic, promoting non-myelinating Schwann cell proliferation and potentially disrupting the nodes/paranodes.