Cellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies

The cell-specific effects of the human remyelination-promoting rHIgM22 on sphingolipid metabolism in cultured glial cells

“…The target antigen of rHIgM22 remained elusive until recently, when we were able to demonstrate that it binds the sulfated glycolipid sulfatide with high speci city in vitro, even if with low binding a nity [6]. This nding is in agreement with previous observations from the group of Moses Rodriguez at Mayo Clinic, showing that rHIgM22 only binds to biological structures (isolated myelin, mouse cerebellar slices) [23] or cultured cells (fully differentiated rodent and human OL, O4-positive CG4 cells) [28] expressing high levels of sulfatide, and that binding was abolished in nervous tissues from mice not expressing cerebroside sulfotransferase, the key enzyme in the biosynthesis of sulfated glycolipids [29]. On the other hand, we showed that in vitro binding of rHIgM22 to sulfatide in lipid monolayers was positively or negatively modulated by the presence of other lipids.…”

The cell-specific effects of the human remyelination-promoting rHIgM22 on sphingolipid metabolism in cultured glial cells

“…The target antigen of rHIgM22 remained elusive until recently, when we were able to demonstrate that it binds the sulfated glycolipid sulfatide with high speci city in vitro, even if with low binding a nity [6]. This nding is in agreement with previous observations from the group of Moses Rodriguez at Mayo Clinic, showing that rHIgM22 only binds to biological structures (isolated myelin, mouse cerebellar slices) [23] or cultured cells (fully differentiated rodent and human OL, O4-positive CG4 cells) [28] expressing high levels of sulfatide, and that binding was abolished in nervous tissues from mice not expressing cerebroside sulfotransferase, the key enzyme in the biosynthesis of sulfated glycolipids [29]. On the other hand, we showed that in vitro binding of rHIgM22 to sulfatide in lipid monolayers was positively or negatively modulated by the presence of other lipids.…”

Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis

“…As yet no common reactivity was identified that would account for the ability of O4, A2B5 and rhIgM22 to induce IFN-β in the CNS. O4 recognizes sulfatide, seminolipid and other targets [30], A2B5 binds multiple c-series gangliosides [72] and rhIgM22 binds one or more unidentified ligands [73]. Notably, O4 and hIgM22 are both natural IgMs with few somatic mutations and we hypothesise their polyreactivity underlies their ability to induce IFN-β in myelinated cultures.…”

A monoclonal natural human IgM protects axons in the absence of remyelination

“…We previously reported that a human IgM monoclonal antibody, HIgM12, bound to the surface of neurons, supported robust neurite extension when presented as a substrate, and overrode the neurite extension inhibition of CNS myelin and myelin-associated glycoprotein (MAG) [ 3 – 5 ]. We also showed that a single 10 mg/kg dose of HIgM12, when peripherally administered, improved clinical disease course of chronic virus-infected mice beginning 2 weeks following treatment, which persisted for 8 weeks [ 6 ].…”

The cell-specific effects of the human remyelination-promoting rHIgM22 on sphingolipid metabolism in cultured glial cells

“…The target antigen of rHIgM22 remained elusive until recently, when we were able to demonstrate that it binds the sulfated glycolipid sulfatide with high speci city in vitro, even if with low binding a nity [6]. This nding is in agreement with previous observations from the group of Moses Rodriguez at Mayo Clinic, showing that rHIgM22 only binds to biological structures (isolated myelin, mouse cerebellar slices) [23] or cultured cells (fully differentiated rodent and human OL, O4-positive CG4 cells) [28] expressing high levels of sulfatide, and that binding was abolished in nervous tissues from mice not expressing cerebroside sulfotransferase, the key enzyme in the biosynthesis of sulfated glycolipids [29]. On the other hand, we showed that in vitro binding of rHIgM22 to sulfatide in lipid monolayers was positively or negatively modulated by the presence of other lipids.…”

Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis

“…As yet no common reactivity was identified that would account for the ability of O4, A2B5 and rhIgM22 to induce IFN-β in the CNS. O4 recognizes sulfatide, seminolipid and other targets [30], A2B5 binds multiple c-series gangliosides [72] and rhIgM22 binds one or more unidentified ligands [73]. Notably, O4 and hIgM22 are both natural IgMs with few somatic mutations and we hypothesise their polyreactivity underlies their ability to induce IFN-β in myelinated cultures.…”

A monoclonal natural human IgM protects axons in the absence of remyelination

“…We previously reported that a human IgM monoclonal antibody, HIgM12, bound to the surface of neurons, supported robust neurite extension when presented as a substrate, and overrode the neurite extension inhibition of CNS myelin and myelin-associated glycoprotein (MAG) [ 3 – 5 ]. We also showed that a single 10 mg/kg dose of HIgM12, when peripherally administered, improved clinical disease course of chronic virus-infected mice beginning 2 weeks following treatment, which persisted for 8 weeks [ 6 ].…”

The cell-specific effects of the human remyelination-promoting rHIgM22 on sphingolipid metabolism in cultured glial cells

“…The target antigen of rHIgM22 remained elusive until recently, when we were able to demonstrate that it binds the sulfated glycolipid sulfatide with high speci city in vitro, even if with low binding a nity [6]. This nding is in agreement with previous observations from the group of Moses Rodriguez at Mayo Clinic, showing that rHIgM22 only binds to biological structures (isolated myelin, mouse cerebellar slices) [23] or cultured cells (fully differentiated rodent and human OL, O4-positive CG4 cells) [28] expressing high levels of sulfatide, and that binding was abolished in nervous tissues from mice not expressing cerebroside sulfotransferase, the key enzyme in the biosynthesis of sulfated glycolipids [29]. On the other hand, we showed that in vitro binding of rHIgM22 to sulfatide in lipid monolayers was positively or negatively modulated by the presence of other lipids.…”

Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis

“…As yet no common reactivity was identified that would account for the ability of O4, A2B5 and rhIgM22 to induce IFN-β in the CNS. O4 recognizes sulfatide, seminolipid and other targets [30], A2B5 binds multiple c-series gangliosides [72] and rhIgM22 binds one or more unidentified ligands [73]. Notably, O4 and hIgM22 are both natural IgMs with few somatic mutations and we hypothesise their polyreactivity underlies their ability to induce IFN-β in myelinated cultures.…”

A monoclonal natural human IgM protects axons in the absence of remyelination

“…We previously reported that a human IgM monoclonal antibody, HIgM12, bound to the surface of neurons, supported robust neurite extension when presented as a substrate, and overrode the neurite extension inhibition of CNS myelin and myelin-associated glycoprotein (MAG) [ 3 – 5 ]. We also showed that a single 10 mg/kg dose of HIgM12, when peripherally administered, improved clinical disease course of chronic virus-infected mice beginning 2 weeks following treatment, which persisted for 8 weeks [ 6 ].…”