The present study was designed to investigate the coupling mechanisms linking the immune and the neuroendocrine corticotropic systems in an integrated defense response triggered by an infectious aggression. The experimental paradigm used consisted of the exploration in individual conscious rats of the temporal pattern of increased plasma concentrations of the two stress hormones, adrenocorticotropic hormone (ACTH) and corticosterone (Cort), and of three cytokines known as ACTH stimulators, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6, after intra-arterial infusions of lipopolysaccharide (LPS) given at three doses, 5 micrograms/kg (LPS-5), 25 micrograms/kg (LPS-25), and 1 mg/kg (LPS-1,000). Blood samples were taken 30 min and immediately before LPS injection (t0) and at 15, 30, 60, 120, 300, and 480 min post-LPS. The three doses of LPS induced ACTH and Cort surges, starting after 30 min for LPS-5 and LPS-25 or 15 min for LPS-1,000 and peaking with a similar amplitude at 60 min before receding slowly to baseline at 480 min for the two lower LPS doses. On the other hand, whatever the LPS dose, none of the three cytokines rose above undetectable basal levels before 60 min. They increased thereafter to culminate 10- to 30-fold above baseline at 60 min (TNF-alpha) or 120 min (IL-1 beta and IL-6) after LPS and declined back to basal levels at 300 min (TNF-alpha, all doses, and IL-6 for LPS-5 and LPS-25). After LPS-25, only IL-1 beta had not regressed to baseline levels at 480 min.(ABSTRACT TRUNCATED AT 400 WORDS)
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.
Conflict of interest: JJD received a research grant from CSL Behring. II holds a patent for dysferlin detection in monocytes (US20030165937A1), and has consulted for Grifols, Genzyme, Alexion, and UCB.
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