The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy

Abstract

In IgM paraproteinemia and peripheral neuropathy, IgM M-protein secretion by B cells leads to a T helper cell response, suggesting that it is antibody-mediated autoimmune disease involving carbohydrate epitopes in myelin sheaths. An immune response against sulfoglucuronosyl glycosphingolipids (SGGLs) is presumed to participate in demyelination or axonal degeneration in the peripheral nervous system (PNS). SGGLs contain a 3-sulfoglucuronic acid residue that interacts with anti-myelin-associated glycoprotein (MAG) and the monoclonal antibody anti-HNK-1. Immunization of animals with sulfoglucuronosyl paragloboside (SGPG) induced anti-SGPG antibodies and sensory neuropathy, which closely resembles the human disease. These animal models might help to understand the disease mechanism and lead to more specific therapeutic strategies. In an in vitro study, destruction or malfunction of the blood-nerve barrier (BNB) was found, resulting in the leakage of circulating antibodies into the PNS parenchyma, which may be considered as the initial key step for development of disease.

Figure 1.

Thin-layer chromatography-immunostaining of GSLs with serum from a patient with IgM paraproteinemia and peripheral neuropathy. Lane 1, bovine brain gangliosides; 2, acidic GSLs isolated from bovine cauda equine; 3, authentic standard sample of SGPG. Plate a was stained with orcinol-sulfuric acid reagent and plate b was immunostained with serum from patient with IgM paraproteinemia and peripheral neuropathy.

Figure 2.

Structures of SGGLs from human cauda equina.

Figure 3.

Electron micrographs of rat sciatic nerve (a) 3 h and (b) 4 days after intraneural injection of anti-SGPG antibodies. (a) A large myelinated axon (Ax) with disintegrating leaflets of myelin (arrows), primarily along the intraperiod line. (b) An electron micrograph of the nodal region of an axon (Ax). To the left, normal appearing paranodal myelin is being stripped away by insinuating macrophage (mφ) processes (arrows) from a degenerating axon (Ax). Numerous macrophages are present in the endoneurial connective tissues. Scale bars: 0.5 µm (a), 2.5 µm (b).

Figure 4.

Effect of anti-L-selectin and anti-SGPG antibodies on the adhesion of human lymphocyes. Filled bars represent IL-1β-activated bovine MECs and the hatched bar represents the nonactivated bovine MEC monolayer. Preincubation with anti-L-selectin and/or anti-SGPG antibody significantly reduced the attachment of human lymphocytes onto the bovine MEC monolayer (*P < 0.05; **P < 0.001). Error bars indicate the SD.