Systemic humoral factors participating in the course of spinal cord injury

Mizrachi, Yossi; Ohry, A; Aviel, A; Rozin, R; Brooks, Moshe Elyakim; Schwartz, Michal

doi:10.1038/sc.1983.48

Cited by 44 publications

(36 citation statements)

References 19 publications

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“…There is strong evidence for molecular mimicry as a mechanism for induction of these antiganglioside Abs in GBS. Clinical data from multiple sclerosis and GBS imply that anti-ganglioside Abs can also be induced secondary to the nervous system injury (Sadatipour et al, 1998;Press et al, 2001), and some experimental and clinical studies suggest that these Abs can be produced secondary to traumatic injury to the nervous system Mizrachi et al, 1983;Hayes et al, 2002). Regardless of the mechanism of Ab induction, our data suggest that inhibition of axon regeneration may be part of the pathobiological spectrum of circulating autoimmune antiganglioside Abs.…”

Section: Discussionmentioning

confidence: 68%

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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Section: Discussionmentioning

confidence: 68%

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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“…Other factors involved in data disparity are level of injury and genetic background; both should be considered and studied in the future. Michal Schwartz's group at the Weizmann Institute of Science provided the first evidence on autoreactive humoral responses against MBP in chronic stages of SCI [6]. They found IgG antibodies against MBP in 68% of the patients with SCI.…”

Section: Discussionmentioning

confidence: 99%

“…The few existing studies have not assessed the humoral and cellular responses in the same group of patients. None of the studies have reported the persistence of a self-reactive response, specifically against MBP, in patients with more than 10 years of injury [5][6][7]. The present work, explored for the first time, the humoral and cellular immune responses against MBP in the same group of individuals.…”

Section: Introductionmentioning

confidence: 96%

Autoreactivity against myelin basic protein in patients with chronic paraplegia

et al. 2011

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Introduction Previous studies have shown the existence of either cellular or humoral MBP-reactive elements up to 5 years after spinal cord injury (SCI), but not the presence of both after 10 years. Materials and methods Twelve SCI patients, with more than 10 years of evolution, and 18 healthy blood donors were studied. Lymphocyte proliferation (colorimetricBrdU ELISA assay) and antibody titers against MBP (ELISA Human IgG MBP-specific assay) were assessed. Results SCI patients presented a significant T-cell proliferation against MBP (lymphocyte proliferation index: 3.7 ± 1.5, mean ± SD) compared to control individuals (0.7 ± 0.3; P \ 0.001). Humoral response analysis yielded a significant difference (P \ 0.0001) between the antibody titers of controls and SCI patients. A significant correlation between cellular and humoral responses was observed. Finally, patients with an ASIA B presented the highest immune responses. Conclusion This work demonstrates, for the first time, the existence of both cellular and humoral responses against MBP in the chronic stages ([10 years) of injury.

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“…Less is known about the role played by antibody-producing B cells. In humans with SCI, elevated titers of myelin-reactive antibodies in serum and cerebrospinal fluid (CSF) suggest that SCI activates T and B cells that recognize CNS proteins (10)(11)(12). Using a clinically relevant murine model of SCI, we have shown that SCI induces a long-lasting B cell response, characterized by enhanced lymphopoiesis in bone marrow and spleen, with increased levels of circulating IgM and IgG antibodies (13).…”

Section: Introductionmentioning

confidence: 96%

“…Currently, the breadth of self/auto antigens recognized by SCIinduced antibodies is not known; however, some will bind CNS proteins and the potential exists for antibody-mediated neurodegeneration (10,11,13). Previously, we showed that microinjection of sera containing SCI antibodies into the intact CNS caused focal inflammation and neurotoxicity (13).…”

Section: Introductionmentioning

confidence: 99%

B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice

Ankeny¹,

Guan²,

Popovich³

2009

J. Clin. Invest.

173

174

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IntroductionThe consequences of neuroinflammation caused by spinal cord injury (SCI) have been inferred mostly from the results of studies that manipulate the function or survival of neutrophils, monocytes/macrophages or T lymphocytes (T cells) (1-9). Less is known about the role played by antibody-producing B cells. In humans with SCI, elevated titers of myelin-reactive antibodies in serum and cerebrospinal fluid (CSF) suggest that SCI activates T and B cells that recognize CNS proteins (10-12). Using a clinically relevant murine model of SCI, we have shown that SCI induces a long-lasting B cell response, characterized by enhanced lymphopoiesis in bone marrow and spleen, with increased levels of circulating IgM and IgG antibodies (13). Activated B cells also accumulate in the injured spinal cord, in which they persist indefinitely (13). Accumulation of intraspinal B cells also is associated with de novo expression of mRNA that encodes a range of autoantibodies (14).Currently, the breadth of self/auto antigens recognized by SCIinduced antibodies is not known; however, some will bind CNS proteins and the potential exists for antibody-mediated neurodegeneration (10, 11, 13). Previously, we showed that microinjection of sera containing SCI antibodies into the intact CNS caused focal inflammation and neurotoxicity (13). Conversely, sera from SCI B cell-knockout mice (BCKO mice), which cannot make antibodies, was innocuous (13). Collectively, these data suggest that activated B cells contribute to the pathological sequelae of SCI, presumably via production of autoantibodies and activation of downstream inflammatory cascades. Here, we prove there is a causal role for B cells as effectors of post-SCI pathology. Specifically, we show that behavioral and anatomical indices of recovery from SCI are improved in BCKO mice and that B cell-mediated pathology is caused by the antibodies they produce. Indeed, antibodies purified from SCI mice cause axon and myelin pathology with transient impairment of motor function. Antibody-mediated pathology is dependent on activation of complement and cells bearing Fc-receptors in the spinal cord. Collectively, these data suggest that con-

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Systemic humoral factors participating in the course of spinal cord injury

Cited by 44 publications

References 19 publications

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

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

Autoreactivity against myelin basic protein in patients with chronic paraplegia

B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice

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