Multifocal motor neuropathy in the Netherlands : immunology, genetics and treatment

Abstract

MMN In a national study on MMN we identified 97 patients. Eighty-eight patients participated in our study. Multivariate analysis showed that axon loss and longer disease duration without IVIg were independent determinants of more severe weakness and disability. IMMUNE PATHOGENESIS Prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum were investigated. Anti-ganglioside IgM antibodies in MMN had a surprisingly limited specificity (against GM1, and occasionally against GD1b and GM2). Therefore, we investigated whether anti-ganglioside antibodies also showed limited clonality. Using light chain analysis of anti-GM1 IgM antibodies, we demonstrated that serum anti-GM1 IgM antibodies in the majority of patients with MMN have the same Ig light chain, suggesting that these antibodies are monoclonal. Patients with anti-GM1 IgM antibodies had more disability, more axon loss and more severe weakness compared to patients without anti-GM1 IgM antibodies.These findings support the assumption that antiganglioside IgM antibodies play a role in MMN pathogenesis. It is not clear whether MMN is a ‘classic’ autoimmune disease (AID). Since different AID often co-occur within patients and their families, we studied the prevalence of AID among MMN patients and their families. In a case-control study encompassing 81 MMN patients and 417 first-degree relatives, and 438 controls and 2,377 first-degree relatives we found that AID are more common in MMN patients (11%) compared to controls (5%). We also studied variation in the activity of the classical and lectin pathway of the complement system in MMN patients and controls. We found no difference in activity of both pathways and complement activity was not associated with outcome of MMN. GENETICS The human leukocyte antigen (HLA) locus is highly heterogeneous, and several HLA alleles have been found associated with AID. A case-control study showed that HLA-DRB1*15 is associated with MMN. Although this finding may support the hypothesis that MMN is a classic AID, we did not find increased frequencies of single nucleotide polymorphisms (SNPs) in genes that are common in a number of other AID. TREATMENT Maintenance treatment with IVIg every few weeks is necessary because the beneficial effects only last a few weeks. A cross-sectional descriptive study showed that IVIg treatment at home is time-saving and reduces the number of days missed at work. Home-treatment is safe and more convenient for most patients. Despite its use, the mechanisms of IVIg that underlie its efficacy in MMN have not been studied in detail. Relevant effector mechanisms of IVIg include anti-idiotype effects, and modulation of B-cell and complement function, among others. We compared the complement-activating properties of anti-GM1 IgM antibodies in sera from MMN patients and disease controls. We showed that anti-GM1 IgM antibodies in sera from MMN patients efficiently activate complement in comparison with disease controls. The addition of IVIg reduced complement deposition significantly. IVIg also reduced concentrations of crucial classical pathway components including C1q in sera of MMN patients. IVIg may thus exert both local and systemic effects on the classical route of the complement system, which may contribute to reduced complement deposition in nerves.