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Unknown humoral factors and some autoantibodies in sera from multifocal motor neuropathy (MMN) patients cause disruption of the blood–nerve barrier (BNB).
MMN is a pure motor neuropathy characterised by asymmetric distal dominant weakness, slowly progressive course and multifocal conduction blocks in nerve conduction studies.1 MMN is included in the list of the differential diagnosis of motor neurone disease because of the presence of atrophy and fasciculation in the affected limbs.
Patients with MMN frequently have elevated levels of immunoglobulin (Ig)M antibodies against ganglioside GM1 in sera.2 High-dose intravenous immunoglobulin and cyclophosphamide have been reported to be effective for the treatment of MMN. It is therefore indicated that immunological mechanism may participate in the pathogenesis of MMN. Although the underlying mechanisms of MMN have not yet been clarified, disruption of the BNB may be one step of the disease process.
In the paper by Shimizu et al,3 the authors show the disruption of BNB by sera from MMN patients. They previously developed the immortalised human peripheral nerve microvascular endothelial cells (PnMECs). The effects of the sera from various diseases on BNB can be evaluated by the addition of the sera samples to the culture medium of PnMECs. The results suggested that some humoral factors other than IgG in MMN sera caused the increased secretion of vascular endothelial growth factor (VEGF) in PnMECs via an autocrine mechanism, leading to the disruption of BNB. In addition, the IgG purified from MMN sera also caused the disruption of the BNB via the increase of VCAM-1 expression. Presence of anti-GM1 antibodies did not influence the BNB function in the PnMECs.
Their data improve the understanding of the pathogenetic mechanisms of MMN. The possibility of the use of natalizumab and neutralising anti-VEGF antibodies in the treatment of MMN might be considered. However, there are still many unsolved issues. In particular, the target molecules on the PnMECs for the unknown factors inducing VEGF secretion and those for the autoantibodies in MMN sera should be identified.
Further investigation is also necessary to identify the factors which actually cause the damage to the peripheral nerves. Anti-GM1 IgM antibodies are among the candidates although they are positive only in about half of the cases. Some other molecules including glycolipids and proteins could be targeted by serum antibodies. Intensive investigation on the cellular immunity also is needed.
Although MMN is considered as an inflammatory neuropathy, steroids and plasmapheresis were ineffective for the treatment of MMN. It suggests that the underlying pathological mechanisms of MMN may be rather different from those of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The authors’ group has already reported that sera from patients with Bickerstaff's brainstem encephalitis and Miller Fisher syndrome did not influence the barrier function in the PnMECs model.4 The effects of the sera from CIDP patients on the BNB function of the same model is needed to clarify whether such disruptive effects are specifically seen in MMN sera or not.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
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