Antibodies to L-periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits.
L-Periaxin is a PDZ-domain protein localized to the plasma membrane of myelinating Schwann cells and plays a key role in the stabilization of mature myelin in peripheral nerves. Mutations in L-periaxin have recently been described in some patients with demyelinating peripheral neuropathy, suggesting that disruption of L-periaxin function may result in nerve injury. In this study, we report the presence of autoantibodies to L-periaxin in sera from two of 12 patients with diabetes mellitus (type 2)-associated neuropathy and three of 17 patients with IgG monoclonal gammopathy of undetermined significance (MGUS) neuropathy, an autoimmune peripheral nerve disorder. By comparison, anti-L-periaxin antibodies were not present in sera from nine patients with IgM MGUS neuropathy or in sera from 10 healthy control subjects. The effect of anti-L-periaxin serum antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-L-periaxin antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly (p < 0.005, n = 3) attenuated sensory-evoked compound muscle action potential (CMAP) amplitudes in the absence of temporal dispersion. In contrast, motor-evoked CMAP amplitudes and latencies were not affected by intraneural injection of sera containing anti-L-periaxin antibody. Light and electron microscopy of anti-L-periaxin serum-injected nerves showed morphologic evidence of demyelination and axon enlargement. Depleting sera of anti-L-periaxin antibodies neutralized the serum-mediated effects on nerve function and nerve morphology. Together, these data support anti-L-periaxin antibody as the pathologic agent in these serum samples. We suggest that anti-L-periaxin antibodies, when present in sera of patients with IgG MGUS- or diabetes-associated peripheral neuropathy, may elicit sensory nerve conduction deficits.
Lawlor
Mike W
MW
Neurology and Research Services, Department of Veterans Affairs, Neurology Service (127)Building 1, Edward Hines Jr Hospital, Hines, IL 60141, USA.
Richards
Michael P
MP
De Vries
George H
GH
Fisher
Morris A
MA
Stubbs
Evan B
EB
D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D001798:Blood Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000276:immunology; D003929:Diabetic Neuropathies / Q000097:blood / Q000150:complications / Q000276:immunology; D006181:H-Reflex / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009431:Neural Conduction / Q000187:drug effects / Q000276:immunology*; D010265:Paraproteinemias / Q000097:blood / Q000150:complications / Q000276:immunology; D010446:Peptide Fragments / Q000032:analysis; D010525:Peripheral Nerves / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000097:blood / Q000150:complications / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
D001323:Autoantibodies; D001798:Blood Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008565:Membrane Proteins; D010446:Peptide Fragments; C086745:periaxin; D003165:Complement System Proteins