Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy

Abstract

We report here on a patient with anti-myelin-associated glycoprotein (MAG) neuropathy in whom examination of a sural nerve biopsy by multichannel confocal microscopy showed a partly overlapping distribution of MAG and IgM deposits in myelinated fibers. Our data demonstrate that MAG in Schmidt-Lanterman incisures and paranodal loops, as well as some additional HNK-1-positive components of the basal lamina, are the major targets of the anti-MAG monoclonal IgM autoantibodies in this neuropathy in vivo. Perforation of the basal lamina can allow the penetration and binding of anti-MAG IgM inside myelinated fibers. Our results support and extend the notion that the production of monoclonal anti-MAG IgM may be antigenically driven by MAG molecules and that this process may occur in the immunologically privileged environment of the nerve prior to the appearance of a genuine gammopathy in serum.

Anti-MAG IgM penetration into myelinated fibers correlates with the extent of myelin widening

“…25 However, we observed in this study IgM deposits not strictly colocalized with MAG, particularly on the basement membrane of the Schwann cells and in compact myelin. These results confirmed previous studies 3,18 showing that anti-MAG IgM antibodies are directed against additional molecules involving other HNK-1-containing components of the basement membrane of myelinating Schwann cells. These HNK-1-containing epitopes could belong to fibronectin, L1, J1/ tenascin, 16 some integrins 19 or sulfoglucuronyl, 12 and chondroitin sulfate proteoglycans.…”

“…23 The role of the anti-MAG antibodies as the main pathogenic factor in the neuropathy has been confirmed by several studies. Gabriel et al 3 recently demonstrated by confocal microscopy that IgM antibody deposits were associated with sites of MAG localization, mainly Schmidt Lanterman incisures and paranodal loops. IgM deposits were additionally localized in the basal lamina of myelin-forming Schwann cells.…”

Anti-SGPG antibody in CIDP: Nosological position of IgM anti-MAG/SGPG antibody-associated neuropathy

“…Valldeoriola et al 22 described a patient with CIDP who initially was negative for IgM anti-MAG antibody but who developed IgM M-protein and anti-MAG antibody activity 2 years later. Some may later develop IgM gammopathy, 11 whereas patients lacking a verifiable IgM gammopathy may have polyneuropathy associated with IgM anti-MAG antibody. 19,23 Patients 4 and 11 (Table 1) without M-protein had very high IgM anti-SGPG antibody titers, IgMs from whom strongly reacted with MAG.…”

Autoantibodies associated with peripheral neuropathy

“…Immunocytochemical investigations of nerve biopsies from such patients demonstrate a selective loss of MAG in many fibers and suggest an important role for the MAG antigen in incisures and paranodal loops. 44,45 However, the induction of neurological signs in rats by immunization with SGPG, as mentioned earlier, suggests that the cross-reacting glycolipid antigens may be very important, because rats do not contain the reactive carbohydrate epitope on myelin proteins but do express low levels of SGPG. The binding of anti-SGPG antibodies to endothelial cells has been suggested to be involved in breakdown of the blood-nerve barrier in these patients.…”