Passive Transfer of IgG Anti-GM1 Antibodies Impairs Peripheral Nerve Repair

López, Pablo H.H.; Zhang, Gang; Zhang, Jiangyang; Lehmann, Helmar C.; Griffin, John W.; Schnaar, Ronald L.; Sheikh, Kazim A.

doi:10.1523/jneurosci.2281-10.2010

Cited by 44 publications

(34 citation statements)

References 66 publications

(95 reference statements)

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“…These clinical observations suggest that anti- ganglioside Abs can adversely affect the nerve repair process in this disease. This hypothesis was strongly supported by our previous studies indicating that experimental and patient-derived anti-ganglioside Abs inhibit axon regeneration in an animal model (Lehmann et al, 2007;Lopez et al, 2010). The current study supports the notion that impaired nerve repair induced by autoantibodies is one mechanism of poor recovery in GBS.…”

Section: Discussionsupporting

confidence: 90%

“…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).…”

Section: Methodsmentioning

confidence: 99%

“…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). The details of these antiganglioside mAbs, including generation, specificity, purification, and designation, were reported previously (Lunn et al, 2000;Gong et al, 2002).…”

Section: Methodsmentioning

confidence: 99%

“…Several studies suggest that some GBS patients with anti-ganglioside Abs directed against GM1, GD1a, or ganglioside complexes have poor prognosis and/or incomplete recovery (Ilyas et al, 1992;Gregson et al, 1993;Simone et al, 1993;Yuki et al, 1993;Jacobs et al, 1996;Bech et al, 1997;Kuwabara et al, 1998a,b;Carpo et al, 1999;Press et al, 2001;Annunziata et al, 2003;Koga et al, 2003;Kaida et al, 2007). We recently demonstrated that experimental monoclonal and GBS patient-derived anti-ganglioside Abs can inhibit regeneration of injured axons in an animal model (Lehmann et al, 2007;Lopez et al, 2010), suggesting that Ab-mediated inhibition of nerve repair is one mechanism of delayed recovery. The cellular and molecular mechanisms of this Ab-mediated inhibition of axon regeneration are not clear.…”

Section: Introductionmentioning

confidence: 97%

“…Patients with residual deficits and significant disability almost always have axonal injury and target denervation; recovery thus requires regeneration from the site of axonal transection. Although the adult mammalian PNS regenerates readily after injury, the mechanisms underlying failure of axon regeneration in GBS cases with permanent neurologic sequelae are beginning to unravel (Lehmann et al, 2007;Lopez et al, 2010;Sheikh and Zhang, 2010).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 90%