The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy (original) (raw)
Related papers
1994
Since a number of anti-glycosphingolipid (GSL) antibody activities have been demonstrated in patients with various neurological disorders, the presence of common antigens between brain microvascular endothelial cells (BMECs) and the nervous tissues presents a potential mechanism for the penetration of macromolecules from the circulation to the nervous system parenchyma. We first investigated GSL composition of cultured bovine BMECs. Bovine BMECs express GM3(NeuAc) and GM3(NeuGc) as the major gangliosides, and GM1, GDla, GDlb, GTlb, as well as sialyl paragloboside and sialyl lactosaminylparagloboside as the minor species. Sulfoglucuronosyl paragloboside was also found to be a component of the BMEC acidic GSL fraction, but its concentration was lower in older cultures. On the other hand, the amounts of neutral GSLs were extremely low, consisting primarily of glucosylceramide. In addition, we analyzed the effect of anti-SGPG IgM antibody obtained from a patient of demyelinative polyneuropathy with macroglobulinemia against cultured BMECs. Permeability studies utilizing cocultured BMEC monolayers and rat astrocytes revealed that the antibody facilitated the leakage of [carboxy-~4C]-inulin and ~25I-labeled human IgM through BMEC monolayers. A direct cytotoxicity of this antibody against BMECs was also shown by a leakage study using p1Cr]incorporated BMECs. This cytotoxicity depended on the concentration of the IgM antibody, and was almost completely blocked by preincubation with the pure antigen, sulfoglucuronosyl paragloboside. Our present study strongly supports the concept that immunological insults against BMECs induce the destruction or malfunction of the blood-nerve barrier, resulting in the penetration of the immunoglobulin molecule to attach peripheral nerve parenchyma.
Autoimmune mechanisms in peripheral neuropathies
Annals of Neurology, 1990
In certain patients with demyelinating neuropathy and plasma cell dyscrasia, there are IgM monoclonal antibodies that recognize a carbohydrate epitope shared by myelin-associated glycoprotein (MAG) and at least two acidic glycolipids in the peripheral nervous system (PNS). The structures of the two acidic lipids have been elucidated as a new class of glycosphingolipids, termed sulfoglucuronyl glycolipids (SGGLs). SGGLs have been demonstrated to be present in myelin, axolemma, and other glia-related membranes in PNS of several animal species, as well as in human dorsal root ganglia and sympathetic ganglia. In rabbits sensitized with sulfoglucuronyl paragloboside (SGPG), a major SGGL in PNS, antibodies developed with reactivities toward SGPG and MAG. The animals also showed moderate weakness, a slowed nerve conduction velocity, and evidence of conduction block. Recently we also found SGPG in rat brain microvessels. This finding supports our hypothesis that autoantibodies may first interact with endothelial cell-bound antigens and that this might change the permeability of the blood-brain or blood-nerve barrier to permit the entry of these autoantibodies into the nervous system. Our data are consistent with the concept that an autoimmune response against the sulfoglucuronyl residue may participate in the pathogenesis of immune-mediated neuropathy.
Anti-MAG and anti-SGPG antibodies in neuropathy
Muscle & Nerve, 1996
We compared the binding of human antibodies from patients with neuropathy to the myelin-associated glycoprotein (MAG), to its cross-reactive glycolipid sulfoglucuronyl paragloboside (SGPG), and to sections of peripheral nerve. Titers were correlated with the clinical presentation and results of electrophysiological and pathological studies. Most patients had a predominantly sensory or sensorimotor demyelinating neuropathy and highly elevated antibodies to both MAG and SGPG, but 2 had highly elevated antibodies to MAG alone, and 1 to SGPG alone. Two patients had predominantly motor neuropathy and highly elevated antibodies to SGPG which reacted with MAG by Western blot but not by enzyme-linked immunosorbent assay. One patient had amyotrophic lateral sclerosis and antibodies to SGPG but not to MAG. These studies indicate that the neuropathic syndrome associated with anti-MAG or -SGPG antibodies are more heterogeneous than previously suspected, and that although most of the antibodies react with both MAG and SGPG, some may react with MAG or SGPG alone. 0
Immunology and Cell Biology, 2000
The common association between monoclonal gammopathy and peripheral neuropathy was studied in seven patients with demyelinating polyneuropathy and IgM paraproteinaemia. Plasma samples from these individuals were thoroughly tested for antiperipheral nerve myelin (PNM) antibodies and then screened for glycoprotein and glycolipid reactivity by western immunoblotting and thin-layer chromatography (TLC) immunostaining. Three of the seven samples showed strong IgM anti-PNM and antisulfatide (GalS) antibody reactivity. Two of these three plasma samples showed extraordinarily high antisulfatide IgM antibody titres, ranging from 1 × 10 4 to 1 × 10 6 arbitrary units/L. These same samples also showed intense myelin staining of sciatic nerve sections (paraffin and cryostat) and teased nerve fibres. No axonal immunoreactivity was observed. These results suggest that high titre IgM antisulfatide antibodies may play a pathogenetic role in the immune demyelination associated with IgM paraproteinaemia.
Journal of Neurochemistry, 1987
Peripheral nerve glycolipids, with which anti-myelin-associated glycoprotein (MAG) antibodies from patients with demyelinating neuropathy and plasma cell dyscrasia cross-react, proved to be novel glycosphingolipids containing a sulfated glucuronyl residue. Consequently, there has been much interest in the immunological role that these sulfated glucuronyl-glycosphingolipids (SGGLs) may play in the pathogenesis of this disorder. For the determination of the distribution of these glycolipids in various nervous tissues and, thereby, the elucidation of their pathogenicity, a quantitative immunostaining-TLC method for their detection has been devised. Using this method, we demonstrated that these glycolipids were distributed in greatly different amounts in the peripheral nerves from human, bovine, chicken, rat, and rabbit. Subcellular localization studies of bovine peripheral nerve also demonstrated that they were enriched in the axolemma-enriched fraction and present in glial-related membranes in lower concentrations. In addition, these glycolipids were present in bovine dura mater and transformed rat Schwann cells. These biochemical results suggest that not only myelin but also axons could be involved as targets of the anti-MAG antibody in macroglobulinemia neuropathy, and it may also be necessary to examine anti-SGGL activity in patients with axonal neuropathy associated with plasma cell dyscrasia.
Journal of the Neurological Sciences, 2001
We previously found that serums with anti-sulfatide antibodies have several different patterns of binding to neural tissue. In this study, Ž . we asked whether serums with anti-myelin associated glycoprotein MAG antibodies also have similar variations in patterns of tissue binding. We examined binding to peripheral nerve in 49 serums with IgM anti-MAG antibodies and 13 serums with IgM anti-sulfoglu-Ž . curonyl paragloboside SGPG antibodies but no MAG binding. We correlated patterns of binding with titers of IgM binding to MAG and SGPG measured by ELISA methods. Our results show that IgM in most anti-MAG serums stained areas of non-compact myelin, including the periaxonal and outer myelin membranes and Schmidt-Lanterman incisures. However, other patterns included IgM binding to areas of compact myelin and to non-myelin structures including axons and endoneurial macrophages. IgM in anti-SGPG serums bound Ž . to axons or macrophages, but rarely to myelin-related structures. A total of 11r62 18% of serums had IgM binding to axons, six with Ž . anti-MAG antibodies and five with anti-SGPG antibodies. The majority of these serums 73% had SGPG titers greater than MAG titers when measured by ELISA. We conclude that anti-MAG serums have several different binding patterns to neural tissue, including axonal binding, especially when anti-MAG antibodies cross-react with SGPG. These different binding patterns may relate to the ability of anti-MAG serum IgM to bind both MAG and SGPG or to other molecules with a sulfated glucuronic acid epitope that are present in peripheral nerve. q
Testing for anti-glycolipid IgM antibodies in chronic immune-mediated demyelinating neuropathies
Journal of the Peripheral Nervous System, 2011
Antibodies to several nerve antigens have been reported in patients with chronic immune-mediated demyelinating neuropathies including chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and IgM paraproteinemic demyelinating polyneuropathy. The association of some reactivities with specific neuropathies, such as IgM antibodies to the myelin-associated glycoprotein in neuropathy associated with IgM monoclonal gammopathy, permitted to cast some light in their pathogenetic mechanisms and introduced new useful tools in their diagnosis. Other antibodies have been variably associated with other forms of neuropathy or with neuropathy itself, casting some doubts on their diagnostic relevance in the workout of these neuropathies. This is particularly true for IgM antibodies to glycolipids, including ganglioside and sulfatides, whose possible role in immune-mediated neuropathies is still debated and will be here reviewed.
Anti‐sulfatide/galactocerebroside antibodies in immunoglobulin M paraproteinemic neuropathies
European Journal of Neurology, 2017
Background and purposeAnti‐sulfatide antibodies have been observed in heterogeneous neuropathies and their clinical relevance is still controversial. Whether the combination of sulfatide with galactocerebroside would increase sensitivity or specificity of enzyme‐linked immunosorbent assay testing compared to sulfatide alone was assessed.MethodsImmunoglobulin M (IgM) antibodies to sulfatides, galactocerebroside and combined sulfatide and galactocerebroside (Sulf/GalC) were measured in 229 neuropathy patients, including 73 with IgM paraproteinemic neuropathy [62 with anti‐myelin‐associated glycoprotein (anti‐MAG) antibody] and 156 with other neuropathies. Results from 27 patients with IgM monoclonal gammopathy without neuropathy and 28 healthy subjects served as control.ResultsThirty‐three patients showed increased titers of anti‐sulfatide antibodies, 28 of whom had an IgM paraproteinemic neuropathy (P < 0.0001). When evaluating the reactivity for the combination Sulf/GalC, 57/229 ...
Mini Review: Immune Response to Myelin-Derived Sulfatide and CNS-Demyelination
Neurochemical Research, 2007
Here we briefly review our understanding of the immune response to myelin-derived glycolipids during an inflammatory autoimmune response in the central nervous system (CNS). We focus primarily on the recognition of the self-glycolipid sulfatide by a distinct population of non-invariant NK T cells. The results of studies we have obtained so far in investigating the presentation of sulfatide by CNS-resident cells including microglia and their interactions with T cells indicate that this pathway might be successfully targeted for the treatment of autoimmune demyelination in multiple sclerosis.
Journal of the Neurological Sciences, 1992
Serum samples from 52 patients with the acute Guillain-Barr~ syndrome (GBS), 19 patients with other neurological disorders, and 18 healthy volunteers were tested for cytotoxicity in cultures of rat Schwann cells and dorsal root ganglion neurons. The samples were also examined by enzyme-linked immunosorbent assay for IgG and IgM antibodies against various acidic and neutral glycolipids. Samples from 16 of the 52 (31%) acute GBS patients and from 1 of the 6 patients with chronic inflammatory demyelinating polyneuropathy produced myelin breakdown in culture. Although 10 of the 16 cytotoxic acute GBS serum samples contained anti-glycolipid immunoglobulins, there was no correlation in individual samples between cytotoxic activity and the presence of antibodies against specific glycolipids. While our results do not exclude a role for anti-glycolipid antibodies in me pathogenesis of the acute GBS, the cytotoxic effects of acute GBS serum in cultures of Schwann cells and sensory neurons are probably not due to these antibodies alone.