Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects

Constance Manso, Luis Querol, Mourad Mekaouche, Isabel Illa, Jérôme J. Devaux
Brain. 2016-03-26; 139(6): 1700-1712
DOI: 10.1093/brain/aww062

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Paranodal axoglial junctions formed by the association of contactin-1,
contactin-associated protein 1, and neurofascin-155, play important functions in
nerve impulse propagation along myelinated axons. Autoantibodies to contactin-1
and neurofascin-155 define chronic inflammatory demyelinating
polyradiculoneuropathy subsets of patients with specific clinical features. These
autoantibodies are mostly of the IgG4 isotype, but their pathogenicity has not
been proven. Here, we investigated the mechanisms how IgG subclasses to
contactin-1 affect conduction. We show that purified anti-contactin-1 IgG1 and
IgG4 bind to paranodes. To determine whether these isotypes can pass the
paranodal barrier, we incubated isolated sciatic nerves with the purified
antibody or performed intraneural injections. We found that IgG4 diffused into
the paranodal regions in vitro or after intraneural injections. IgG4 infiltration
was slow and progressive. In 24 h, IgG4 accessed the paranode borders near the
nodal lumen, and completely fill the paranodal segments by 3 days. By contrast,
control IgG, anti-contactin-1 IgG1, or even anti-contactin-associated-protein-2
IgG4 did not pass the paranodal barrier. To determine whether chronic exposure to
these antibodies is pathogenic, we passively transferred anti-contactin-1 IgG1
and IgG4 into Lewis rats immunized with P2 peptide. IgG4 to contactin-1, but not
IgG1, induced progressive clinical deteriorations combined with gait ataxia. No
demyelination, axonal degeneration, or immune infiltration were observed.
Instead, these animals presented a selective loss of the paranodal specialization
in motor neurons characterized by the disappearance of the contactin-associated
protein 1/contactin-1/neurofascin-155 complex at paranodes. Paranode destruction
did not affect nodal specialization, but resulted in a moderate node lengthening.
The sensory nerves and dorsal root ganglion were not affected in these animals.
Electrophysiological examination further supported these results and revealed
strong nerve activity loss affecting predominantly small diameter or slow
conducting motor axons. These deficits partly matched with those found in
patients: proximal motor involvement, gait ataxia, and a demyelinating neuropathy
that showed early axonal features. The animal model thus seemed to replicate the
early deteriorations in these patients and pointed out that paranodal loss in
mature fibres results in conduction defects, but not conduction slowing. Our
findings indicate that IgG4 directed against contactin-1 are pathogenic and are
reliable biomarkers of a specific subset of chronic inflammatory demyelinating
polyneuropathy patients. These antibodies appear to loosen the paranodal barrier,
thereby favouring antibody progression and causing paranodal collapse.


Auteurs Bordeaux Neurocampus