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Home arrow Environment arrow Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management

Humoral Immunity

Different lines of evidence suggest that humoral immunity has an important role in the pathogenesis of CIDP. Firstly, sural nerve biopsies of some patients with CIDP have shown complement and immunoglobulin deposition on the surface of Schwann cells and compact myelin [117, 118]; secondly, serum proteins from CIDP patients bind to the segments of healthy nerves, which results in demyelination and conduction blocks, when injected interneurally [119]; thirdly, the efficacy of plasma exchange in the treatment of CIDP implicates the important role of humoral factors in its pathogenesis.

It is therefore plausible that after the BNB is first damaged by the action of T cells and macrophages detailed above, autoantibodies mediate demyelination by complement fixation and by directing macrophages to the antigenic targets via Fc receptors, leading to opsonization and phagocytosis.

Although the target antigen in CIDP remains elusive, antibodies to a number of myelin and axonal antigens such as glycolipids GM1, LM1, and LM1-containing ganglioside complex, beta tubulin, galactocerebroside, chondroitin sulfate, and proteins P0, P2, and P0-related glycoprotein have been reported in sera from CIDP patients [120, 121]. On the other hand, these antibodies have not been detected in most patients with CIDP, and only antibodies against PO were shown to be pathogenic in vivo with passive transfer or intraneural injection [122]. The presence of these autoantibodies may represent an epiphenomenon of the ongoing inflammation rather than denote causality.

Proteins in the non-compact myelin in the nodal, paranodal, and juxtanodal regions have an important role for the maintenance of structural integrity of the nodes of Ranvier and therefore saltatory conduction. As the search for a target antigen among major compact myelin proteins has been so far unsuccessful, the attention has shifted toward non-compact myelin proteins such as gliomedin, neurofascin, contactin, and Caspr 1 [40, 123, 124]. The complex of contactin/Caspr/neurofas- cin-155 has a critical function in the integrity of paranodal junctions [125]. In a study by Deveaux et al., 30% of patients with CIDP had IgG antibodies that bound to the nodes of Ranvier and paranodes of the rodent nerves, and the binding was specific to gliomedin, neurofascin 186, and contactin [123]. Another study showed that 13 of 533 Japanese patients with CIDP had an IgG4 antibody to contactin 1; seropositivity was associated with sensory ataxia and poor responsiveness to IVIG treatment [126]. In another study and using the same group of patients, antibodies to neurofascin-155 were identified in 7% of the patients [127]; those who were seropositive were more likely to have sensory ataxia (42%), tremors (13%), and demyelinating CNS lesions (8%) and also were poorly responsive to IVIG [127]. Poor response to IVIG in patients positive to neurofascin-155 and contactin 1 has been suggested to be due to the fact that antibodies are of IgG4 type, which do not result in complement fixation and have low affinity to Fc receptors, two postulated immunomodulatory mechanisms of IVIG [127].

Antibodies to contactin/Caspr/neurofascin-155 complex are pathogenic as serum of anti-contactin-positive CIDP patients prevents adhesive interaction between contactin. Caspr and neurofascin-155 therefore alter the structure of paranodal junctions in myelinated neuronal culture [125].

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