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

By Toshio ARIGA


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

Topics: Review
Publisher: The Japan Academy
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Provided by: PubMed Central

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  1. (1987). (94) Cultured microvascular endothlial cells 0.06 —
  2. (1991). A carbohydrate epitope defined by monoclonal antibody VC1.1 is found on N-CAM and other cell adhesion molecules. Brain Res.
  3. (1981). A differentiation antigen of human NK and K cells identified by a monoclonal antibody (HNK-1).
  4. (1991). A lymphocyte homing receptor (Lselectin) mediates the in vitro attachment of lymphocytes to myelinated tracts of the central nervous system.
  5. (1992). A novel glucuronyltransferase in nervous system presumably associated with the biosynthesis of HNK-1 carbohydrate epitope on glycoproteins.
  6. (2002). A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy.
  7. (2011). accepted May 13, 2011) SGGLs in IgM paraproteinemia and peripheral neuropathy No. 7] 403Profile Toshio Ariga was born in
  8. (1991). Adhesion of primary Schwann cells to HNK-1 reactive glycosphingolipids. Cellular specificity.
  9. (1984). Angiopathic neuropathy in connective tissue disease.
  10. (1996). Anti-MAG and anti-SGPG antibodies in neuropathy.
  11. (1995). Anti-MAG antibody-associated polyneuropathies: improvement following immunotherapy with monthly plasma exchange and IV cyclophosphamide.
  12. (1986). Antibodies to glycolipids in demyelinating diseases of the human peripheral nervous system.
  13. (2009). Antiganglioside antibodies and their pathophysiological effects on Guillain–Barré syndrome and related disorders—a review.
  14. (1999). Autoantibodies associated with peripheral neuropathy.
  15. (1991). Biosynthesis in vitro of GlcA O 1-3nLcOse4Cer by a novel glucuronyltransferase (GlcAT-1) from embryonic chicken brain.
  16. (1990). Carbohydrates and carbohydrate-binding proteins in the nervous system.
  17. (2002). cDNA cloning, genomic structure and chromosomal mapping of the mouse glucuronyltransferase-S involved in the biosynthesis of the HNK-1 carbohydrate epitope.
  18. (1988). Cell adhesion molecules in vertebrate neural development.
  19. (1993). Characterization and developmental expression of a novel sulfotransferase for the biosynthesis of sulfoglucuronyl glycolipids in the nervous system.
  20. (1994). Characterization and developmental expression of lactotriosylceramide: galactosyltransferase for the synthesis of neolactotetraosylceramide in the nervous system.
  21. (1992). Characterization of a glucuronyltransferase: neolactotetraosylceramide glucuronyltransferase from rat brain.
  22. (1997). Characterization of a sulfoglucuronyl carbohydrate binding protein in the developing nervous system.
  23. (1990). Characterization of solubilized GlcAT-1 (UDP-GlcA: nLcOse4Cer beta 1-3 glucuronyltransferase) activity from embryonic chicken brain and its inhibition by Derythro-sphingosine.
  24. (1987). Characterization of sulfated glucuronic acid containing glycolipids reacting with IgM M-proteins in patients with neuropathy.
  25. (1989). Characterization of two glucuronic acidcontaining glycosphingolipids in larvae of the green-bottle fly, Lucilia caesar.
  26. (2003). Chronic neuropathy with IgM anti-ganglioside antibodies: lack of long term response to rituximab.
  27. (2000). Cloning and chromosomal mapping of human glucuronyltransferase involved in biosynthesis of the HNK-1 carbohydrate epitope.
  28. (1999). Cloning and expression of a novel galactoside O1, 3-glucuronyltransferase involved in the biosynthesis of HNK-1 epitope.
  29. (1997). Cloning and functional expression of a novel glucuronyltransferase involved in the biosynthesis of the carbohydrate epitope HNK-1.
  30. (2006). Crystal structure of GlcAT-S, a human glucuronyltransferase, involved in the biosynthesis of the HNK-1 carbohydrate epitope.
  31. (2002). Crystal structure of O 1,3-glucuronyltransferase I in complex with active donor substrate UDP-GlcUA.
  32. (1988). Demyelination induced by intraneural injection of human antimyelin-associated glycoprotein antibodies.
  33. (1994). Determination of structural elements of the L2/HNK-1 carbohydrate epitope required for its function.
  34. (2007). Developmental changes of glycosphingolipids and expression of glycogenes in mouse brains.
  35. (1991). Developmental expression of HNK-1-reactive antigens in rat cerebral cortex and molecular heterogeneity of sulfoglucuronylneolactotetraosylceramide in CNS versus PNS.
  36. (1990). Developmental expression of HNK-1-reactive antigens in the rat cerebellum and localization of sulfoglucuronyl glycolipids in molecular layer and deep cerebellar nuclei.
  37. (2005). Different acceptor specificities of two glucuronyltransferases involved in the biosynthesis of HNK-1 carbohydrate.
  38. (2000). Differential expression of two glucuronyltransferases synthesizing HNK-1 carbohydrate epitope in the sublineages of the rat myogenic progenitors.
  39. (1994). Distal accentuation of conduction slowing in polyneuropathy associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
  40. (2007). Distributions of glucuronyltransferases, GlcAT-P and GlcAT-S, and their target substrate, the HNK-1 carbohydrate epitope in the adult mouse brain with or without a targeted deletion of the GlcAT-P gene.
  41. (1990). Effect of different fixatives on immunocytochemical localization of HNK-1-reactive antigens in cerebellum: a method for differentiating the localization of the same carbohydrate epitope on proteins vs lipids.
  42. (1987). Experimental demyelination of nerve induced by serum of patients with neuropathy and an anti-MAG IgM M-protein.
  43. (1994). Expression and biological functions of sulfoglucuronyl glycolipids (SGGLs) in the nervous system—a review.
  44. (1991). Expression and regulation of UDP-glucuronate: neolactotetraosylceramide glucuronyltransferase in the nervous system.
  45. (2000). Expression and role of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein SBP-1 in developing rat cerebral cortex.
  46. (1997). Expression cloning of a cDNA encoding a sulfotransferase involved in the biosynthesis of the HNK-1 carbohydrate epitope.
  47. (1989). Focal myelin thickenings in a peripheral neuropathy associated with IgM monoclonal gammopathy.
  48. (1997). for the IgM-associated Polyneuropathy Study Group
  49. (1994). Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy.
  50. (1996). Generation and characterization of antisulfoglucuronosyl paragloboside monoclonal antibody NGR50 and its immunoreactivity with peripheral nerve.
  51. (2008). Glucuronylation in Escherichia coli for the bacterial synthesis of the carbohydrate moiety of nonsulfated HNK-1.
  52. (2001). Glycosphingolipid antigen and blood-nerve barrier. Recent Res.
  53. (1994). Glycosphingolipid antigens in cultured bovine brain microvascular endothelial cells: sulfoglucuronosyl paragloboside as a target of monoclonal IgM in demyelinative neuropathy [corrected].
  54. (2008). Glycosphingolipid antigens in neural tumor cell lines and anti-glycosphingolipid antibodies in sera of patients with neural tumors.
  55. (2004). Glycosphingolipid composition of primary cultured human brain microvascular endothelial cells.
  56. (2006). guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
  57. (2002). HNK-1 sulfotransferase null mice express glucuronyl glycoconjugates and show normal cerebellar granule neuron migration in vivo and in vitro.
  58. (1993). Human peripheral myelin protein-22 carries the L2/HNK-1 carbohydrate adhesion epitope.
  59. (1984). Identical reactivity of monoclonal antibodies HNK-1 and NC-1: conservation in vertebrates on cells derived from the neural primordium and on some leukocytes.
  60. (1984). IgM in a human neuropathy related to paraproteinemia binds to a carbohydrate determinant in the myelin-associated glycoprotein and to a ganglioside.
  61. (2004). IgM paraproteinaemic neuropathies.
  62. (1988). Immunocytological localization of the major peripheral nervous system glycoprotein P0 and the L2/HNK-1 and L3 carbohydrate structures in developing and adult mouse sciatic nerve.
  63. (1984). Indication of a possible role in a demyelinating neuropathy for an antigen shared between myelin and NK cells.
  64. (1991). Induction of demyelination by intraneural injection of antibodies against sulfoglucuronyl paragloboside.
  65. (2008). Induction of experimental ataxic sensory neuronopathy in cats by immunization with purified
  66. (1988). Inhibition of allergic encephalomyelitis in rats by treatment with sulfated polysaccharides.
  67. (1992). Insect glial cells show differential expression of a glycolipid-derived, glucuronic acid-containing epitope throughout neurogenesis: detection during postembryogenesis and regeneration in the central nervous system of Tenebrio molitor
  68. (1995). Interleukin 1 O up-regulates the expression of sulfoglucuronosyl paragloboside, a ligand for Lselectin, in brain microvascular endothelial cells.
  69. (1991). Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins.
  70. (1996). Link between peripheral neuropathy and monoclonal dysglobulinemia: a study of 66 cases.
  71. (1987). Localization of glycoconjugates recognized by the HNK-1 antibody in mouse and chick embryos during early neural development.
  72. (1990). Localization of sulfated glucuronyl glycolipids in human dorsal root and sympathetic ganglia. Brain Res.
  73. (2000). Long-term prognosis of neuropathy associated with anti-MAG IgM Mproteins and its relationship to immune therapies.
  74. (2002). Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning.
  75. (1984). Microangiopathy of vasa nervorum in dysglobulinemic neuropathy.
  76. (1999). Molecular cloning and expression of a second glucuronyltransferase involved in the biosynthesis of the HNK-1 carbohydrate epitope.
  77. (1998). Molecular cloning and expression of glucuronyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans.
  78. (2002). Molecular cloning and genomic analysis of mouse glucuronyltransferase involved in biosynthesis of the HNK-1 epitope.
  79. (1992). Monoclonal antibody BM89 recognizes a novel cell surface glycoprotein of the L2/HNK-1 family in the developing mammalian nervous system.
  80. (2003). Monoclonal gammopathies of undetermined significance: a review.
  81. (1982). Myelin-associated glycoprotein is the antigen for a monoclonal IgM in polyneuropathy.
  82. (1996). N-Acetylglucosaminyl transferase regulates the expression of the sulfoglucuronyl glycolipids in specific cell types in cerebellum during development.
  83. (1984). Neural cell adhesion molecules and myelinassociated glycoprotein share a common carbohydrate moiety recognized by monoclonal antibodies L2 and HNK-1.
  84. (1998). Neuropathies associated with paraproteinemia.
  85. (1998). On the specificity of anti-sulfoglucuronosyl glycolipid antibodies.
  86. (1995). Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies.
  87. (2010). Pathogenesis and Treatment of Anti-MAG Neuropathy.
  88. (2002). Peripheral neuropathies and anti-glycolipid antibodies.
  89. (2008). Peripheral neuropathies associated with monoclonal gammopathies of undetermined significance.
  90. (1988). Peripheral neuropathy and anti-MAG antibodies.
  91. (1987). Peripheral neuropathy associated with monoclonal IgM autoantibody.
  92. (1983). Peripheral neuropathy with IgM kappa monoclonal immunoglobulin directed against myelinassociated glycoprotein.
  93. (1987). Perturbation of cranial neural crest migration by the HNK-1 antibody.
  94. (1980). Plasma-cell dyscrasia and peripheral neuropathy with a monoclonal antibody to peripheral-nerve myelin.
  95. (1985). Polyneuropathy and IgM monoclonal gammopathy: studies on the pathogenetic role of anti-myelin-associated glycoprotein antibody.
  96. (1984). Polyneuropathy in Waldenstrom’s macroglobulinaemia: reduction of endoneurial IgM-deposits after treatment with chlorambucil and plasmapheresis.
  97. (1991). Preliminary studies on sensitization of Lewis rats with sulfated glucuronyl paragloboside. Brain Res.
  98. (1988). Preparation and characterization of antibodies against a sulfated glucuronic acid-containing glycosphingolipid.
  99. (1981). Prevalence of monoclonal protein in peripheral neuropathy.
  100. (1998). Purification and characterization of a glucuronyltransferase involved in the biosynthesis of the HNK-1 epitope on glycoproteins from rat brain.
  101. (2004). Purification and characterization of two recombinant human glucuronyltransferases involved in the biosynthesis of HNK-1 carbohydrate in Escherichia coli.
  102. (1988). Reactivity with the peripheral myelin glycoprotein P0 in serum from patients with monoclonal IgM gammopathy and polyneuropathy.
  103. (1983). Recognition of myelin-associated glycoprotein by the monoclonal antibody HNK-1.
  104. (2002). Regional expression of inducible nitric oxide synthase in the kidney stimulated by lipopolysaccharide in the rat.
  105. (1985). Regulation of O-D-galactoside , 2!3 sialyltransferase activity. The effects of detergents and lysophosphatidates.
  106. (2001). Regulation of sulfoglucuronyl glycolipid synthesis in the developing rat sciatic nerve.
  107. (1996). Sensitization of Lewis rats with sulfoglucuronosyl paragloboside: electrophysiological and immunological studies of an animal model of peripheral neuropathy.
  108. (1992). SGGLs in IgM paraproteinemia and peripheral neuropathy No.
  109. (2004). Structural basis for acceptor substrate recognition of a human glucuronyltransferase, GlcAT-P, an enzyme critical in the biosynthesis of the carbohydrate epitope HNK-1.
  110. (1985). Structure of a glycolipid reacting with monoclonal IgM in neuropathy and with HNK-1.
  111. (1986). Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy.
  112. (1994). Subcellular distribution of sulfated glucuronyl glycolipids in human peripheral motor and sensory nerves.
  113. (1987). Subcellular localization of sulfated glucuronic acid-containing glycolipids reacting with anti-myelin-associated glycoprotein antibody.
  114. (1987). Sulfated glucuronic acid-containing glycoconjugates are temporally and spatially regulated antigens in the developing mammalian nervous system.
  115. (1993). Sulfated glucuronyl glycolipids and gangliosides in the optic nerve of humans.
  116. (1986). Sulfated glucuronyl glycolipids reacting with anti-myelin-associated glycoprotein monoclonal antibodies including IgM paraproteins in neuropathy: species distribution and partial characterization of epitopes. Brain Res.
  117. (1990). Sulfated glucuronyl paragloboside in rat brain microvessels.
  118. (1998). Sulfoglucuronosyl glycolipids as putative antigens for autoimmune inner ear disease.
  119. (2009). Sulfoglucuronosyl paragloboside is a ligand for T cell adhesion: regulation of sulfoglucuronosyl paragloboside expression via nuclear factor 5B signaling.
  120. (1987). Sulfoglucuronyl-neolacto series of glycolipids in peripheral nerves reacting with HNK-1 antibody.
  121. (1993). Synthesis of sulfated glucuronyl glycosphingolipids; carbohydrate epitopes of neural cell-adhesion molecules.
  122. (1996). Synthetic studies on sialoglycoconjugates 90: Total synthesis of sulfated glucuronyl paraglobosides.
  123. (2006). Synthetic sulfated glucuronosyl paragloboside (SGPG) and its use for the detection of autoimmune peripheral neuropathies.
  124. (1982). The effect of linoleic acid and benzyl alcohol on the activity of glycosyltransferases of rat liver Golgi membranes and some soluble glycosyltransferases.
  125. (1964). The Gangliosides.
  126. (1993). The HNK1 reactive sulfoglucuronyl glycolipids are ligands for L-selectin and P-selectin but not E-selectin.
  127. (1992). The L2/HNK-1 carbohydrate epitope is involved in the preferential outgrowth of motor neurons on ventral roots and motor nerves.
  128. (1988). The L2/HNK-1 carbohydrate of neural cell adhesion molecules is involved in cell interactions.
  129. (1984). The monoclonal antibody HNK-1 reacts with a human peripheral nerve ganglioside.
  130. (1985). The neuropathy of plasma cell dyscrasia: binding of IgM M-proteins to peripheral nerve glycolipids.
  131. (1977). The nomenclature of lipids.
  132. (1998). The role of glycosphingolipids in neurological disorders. Mechanisms of immune action.
  133. (2003). Treatment of IgM antibody associated polyneuropathies using rituximab.
  134. (2007). Tumor necrosis factor-, up-regulates glucuronosyltransferase gene expression in human brain endothelial cells and promotes T-cell adhesion.
  135. (2001). Variability in immunohistochemistries of IgM M-proteins binding to sulfated glucuronyl paragloboside.
  136. (1999). Variability in the binding of anti-MAG and anti-SGPG antibodies to target antigens in demyelinating neuropathy and IgM paraproteinemia.
  137. (1998). Waldenstrom’s macroglobulinemia: incidence patterns in the United States,