High‐Affinity Anti‐Ganglioside IgG Antibodies Raised in Complex Ganglioside Knockout Mice

Lunn, Michael P.; Johnson, Lisa M.; Fromholt, Susan; Itonori, Saki; Huang, Jian; Vyas, Alka; Hildreth, James E. K.; Griffin, John W.; Schnaar, Ronald L.; Sheikh, Kazim A.

doi:10.1046/j.1471-4159.2000.0750404.x

Cited by 92 publications

(71 citation statements)

References 32 publications

(40 reference statements)

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“…(B) RSNA responses for each rat in the study. from living neurons in culture without toxicity, reversing MAGmediated axon outgrowth inhibition in some nerve cell types (17,34). Intrathecal infusion of 2 U/mL of V. cholerae sialidase in the current studies did not result in toxicity and effectively cleared sialoglycans from a large area of spinal cord tissue surrounding the infusion site.…”

Section: Discussionmentioning

confidence: 64%

Sialidase enhances recovery from spinal cord contusion injury

Mountney¹,

Zahner

Lorenzini³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Axons fail to regenerate in the injured spinal cord, limiting motor and autonomic recovery and contributing to long-term morbidity. Endogenous inhibitors, including those on residual myelin, contribute to regeneration failure. One inhibitor, myelin-associated glycoprotein (MAG), binds to sialoglycans and other receptors on axons. MAG inhibition of axon outgrowth in some neurons is reversed by treatment with sialidase, an enzyme that hydrolyzes sialic acids and eliminates MAG-sialoglycan binding. We delivered recombinant sialidase intrathecally to rats following a spinal cord contusive injury. Sialidase (or saline solution) was infused to the injury site continuously for 2 wk and then motor behavior, autonomic physiology, and anatomic outcomes were determined 3 wk later. Sialidase treatment significantly enhanced hindlimb motor function, improved bulbospinally mediated autonomic reflexes, and increased axon sprouting. These findings validate sialoglycans as therapeutic targets and sialidase as a candidate therapy for spinal cord injury.axon regeneration | ganglioside | myelin-associated glycoprotein | serotonergic axons | sialoglycan

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Section: Discussionmentioning

confidence: 64%

Sialidase enhances recovery from spinal cord contusion injury

Mountney¹,

Zahner

Lorenzini³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Two IgG monoclonal Abs (mAbs) were used in this study because they have been tested previously in an animal model of axonal regeneration (Lehmann et al, 2007;Lopez et al, 2010). Anti-GD1a/GT1b IgG2b (GD1a/GT1b-2b) mAb is prototypic Ab, which has been extensively characterized in our previous studies (Lunn et al, 2000;Gong et al, 2002;Zhang et al, 2004), including its capacity to severely inhibit axon regeneration in an animal model (Lehmann et al, 2007). This mAb was compared with anti-GM1 IgG2b mAb (GM1-2b), which does not induce inhibition of axon regeneration in the same animal model (Lopez et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…This mAb was compared with anti-GM1 IgG2b mAb (GM1-2b), which does not induce inhibition of axon regeneration in the same animal model (Lopez et al, 2010). The details of these antiganglioside mAbs, including generation, specificity, purification, and designation, were reported previously (Lunn et al, 2000;Gong et al, 2002). An irrelevant mouse IgG-2b mAb (Abcam) was used as a negative control Ab.…”

Section: Methodsmentioning

confidence: 99%

Anti-Ganglioside Antibody-Mediated Activation of RhoA Induces Inhibition of Neurite Outgrowth

Zhang¹,

Lehmann

Manoharan

et al. 2011

J. Neurosci.

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Anti-ganglioside antibodies (Abs) are strongly associated with axonal forms of Guillain Barré syndrome (GBS). Some studies indicate that these Abs, including those with GD1a reactivity, are associated with poor prognosis and/or incomplete recovery. We recently demonstrated that a disease-relevant anti-ganglioside Ab with GD1a reactivity inhibits axon regeneration after PNS injury in an animal model (Lehmann et al., 2007). An implication of these findings is that anti-GD1a Abs can mediate inhibition of axon regeneration and limit recovery in some patients with GBS. The downstream inhibitory intracellular signaling that mediates anti-ganglioside Ab-induced axon inhibition remains unclear. In the current study, we show that disease-relevant and GBS patient's anti-ganglioside Abs can inhibit neurite outgrowth in dissociated primary neuronal cultures. Activation of small GTPase RhoA and its key downstream effector Rho kinase (ROCK) are critical mediators of growth cone and neurite outgrowth inhibition. Therefore, we examined the role of these intracellular signaling molecules in our primary neuronal cultures by molecular and pharmacologic approaches. Our results show that the Ab-mediated inhibition of neurite outgrowth involves the activation of RhoA and ROCK pathway and this activation is through the engagement of specific cell-surface gangliosides by Abs. In summary, these studies directly link patient autoantibodies to an intracellular inhibitory signaling pathway involved in anti-ganglioside Abmediated inhibition of neurite outgrowth.

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“…A previously well characterized monoclonal antibody (mAb) GD1a/GT1b IgG2b (GD1a/GT1b-2b) was used for all passive transfer studies because it binds to both myelinated and unmyelinated axons in peripheral nerves (Gong et al, 2002), its pathobiological effects depend on expression of corresponding specific gangliosides Zhang et al, 2004;Goodfellow et al, 2005), and it induces mild complementdependent neuropathy in an animal model . The generation, specificity, production, and purification of this mAb were reported previously (Lunn et al, 2000;Gong et al, 2002). GD1a/GT1b-2b in ascites (Covance, Princeton, NJ) (n ϭ 4), or hollow fiber supernatant (Johns Hopkins Cell Culture Facility) (n ϭ 3), or purified Ab (n ϭ 2), was used for the passive immunization of wildtype animals.…”

Section: Methodsmentioning

confidence: 99%

Passive Immunization with Anti-Ganglioside Antibodies Directly Inhibits Axon Regeneration in an Animal Model

Lehmann¹,

López²,

Zhang³

et al. 2007

J. Neurosci.

108

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Recent studies have proposed that neurite outgrowth is influenced by specific nerve cell surface gangliosides, which are sialic acidcontaining glycosphingolipids highly enriched in the mammalian nervous system. For example, the endogenous lectin, myelinassociated glycoprotein (MAG), is reported to bind to axonal gangliosides (GD1a and GT1b) to inhibit neurite outgrowth. Clustering of gangliosides in the absence of inhibitors such as MAG is also shown to inhibit neurite outgrowth in culture. In some human autoimmune PNS and CNS disorders, autoantibodies against GD1a or other gangliosides are implicated in pathophysiology. Because of neurobiological and clinical relevance, we asked whether anti-GD1a antibodies inhibit regeneration of injured axons in vivo. Passive transfer of anti-GD1a antibody severely inhibited axon regeneration after PNS injury in mice. In mutant mice with altered ganglioside or complement expression, inhibition by antibodies was mediated directly through GD1a and was independent of complement-induced cytolytic injury. The impaired regenerative responses and ultrastructure of injured peripheral axons mimicked the abortive regeneration typically seen after CNS injury. These data demonstrate that inhibition of axon regeneration is induced directly by engaging cell surface gangliosides in vivo and imply that circulating autoimmune antibodies can inhibit axon regeneration through neuronal gangliosides independent of endogenous regeneration inhibitors such as MAG.

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High‐Affinity Anti‐Ganglioside IgG Antibodies Raised in Complex Ganglioside Knockout Mice

Abstract: Gangliosides, sialic acid-bearing glycosphingolipids, are highly enriched in the vertebrate nervous system.

Cited by 92 publications

References 32 publications

Sialidase enhances recovery from spinal cord contusion injury

Sialidase enhances recovery from spinal cord contusion injury

Anti-Ganglioside Antibody-Mediated Activation of RhoA Induces Inhibition of Neurite Outgrowth

Passive Immunization with Anti-Ganglioside Antibodies Directly Inhibits Axon Regeneration in an Animal Model

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