Monomeric IgG Is Neuroprotective via Enhancing Microglial Recycling Endocytosis and TNF-α

Hulse, Raymond E.; Swenson, Wade G.; Kunkler, Phillip E.; White, David M.; Kraig, Richard P.

doi:10.1523/jneurosci.3856-08.2008

Cited by 46 publications

(98 citation statements)

References 67 publications

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“…Indeed, antibodies purified from naive or sham-injured mice are benign when they are injected into normal spinal cord or brain. Natural autoantibodies exist in these preparations and likely help coordinate neuroprotective functions in microglia and macrophages, including the induction of recycling endocytosis and TNF-α release, ligation of antiinflammatory FcRs, and induction of remyelination via stimulation of oligodendrocyte progenitor cells (50)(51)(52)(53)(54). These functions predominate when antibody concentrations are low or when antibodies exist in monomeric form, i.e., not bound to antigen (50).…”

Section: Figurementioning

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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Section: Figurementioning

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

View full text Add to dashboard Cite

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“…cLTD was evoked by 20 min exposure to Ringer's solution containing 100 µM of RS-3,5-dihydroxyphenyl-glycine at 37 °C (Volk et al 2006). sTNFR1 (200 ng/mL) was applied to cultures 30 min before cLTP and after cLTP induction but was excluded from maximal injury aspects of the excitotoxicity paradigms which followed previous descriptions (Hulse et al 2008). ] FIGURE 7.…”

Section: Figure 6 Legend Continued On Next Page Tnf-α and Microglial mentioning

confidence: 99%

“…This amplification was removed by abrogation of TNF-α signaling via sTNFR1 inclusion (not shown). Results adapted with permission from Hulse et al 2008. tional adaptation necessary for EE-based neuroprotection. However, the precise nature of these adaptive processes and their relation to TNF-α and microglial activation remain undefined.…”

Section: Tnf-α and Microglial Hormesis From Brain Activity Figure 7 Lmentioning

confidence: 99%

TNF-α and Microglial Hormetic Involvement in Neurological Health & Migraine

et al. 2010

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Environmental enrichment, i.e., increased intellectual, social, and physical activity makes brain more resilient to subsequent neurological disease. The mechanisms for this effect remain incompletely defined, but evidence shows tumor necrosis factor-alpha (TNF-α) is involved. TNF-α, at acutely high levels, possesses the intrinsic capacity to enhance injury associated with neurological disease. Conversely, the effect of TNF-α at low-levels is nutritive over time, consistent with physiological conditioning hormesis. Evidence shows that neural activity triggers low-level pro-inflammatory signaling involving TNF-α. This low-level TNF-α signaling alters gene expression, resulting in an enhanced resilience to disease. Brain-immune signaling may become maladaptive when increased activity is chronic without sufficient periods of reduced activity necessary for nutritive adaptation. Such tonically increased activity may explain, for example, the transformation of episodic to chronic migraine with related increased susceptibility to spreading depression, the most likely underlying cause of this malady. Thus, TNF-α, whose function is to alter gene expression, and its principal cellular source, microglia, seem powerfully positioned to orchestrate hormetic immune signaling that establishes the phenotype of neurological health and disease from brain activity.

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“…These data clearly show that cortical rat neurons can produce IgG. Under physiologic conditions, there is 16 ± 2 μg/ml IgG in the CSF (Hulse et al 2008) and this may be derived from neurons.…”

Section: Discussionmentioning

confidence: 56%

“…At physiological levels, exogenous monomeric IgG is protective of neurons via enhancement of endocytotic recycling, and release of microglial TNF-α following binding to FcγRs (Hulse et al 2008). IgG also takes part in neural development by inducing the differentiation of oligodendrocyte precursor cells (OPC) into myelinating oligodendrocytes through the activation of Fyn tyrosine kinase by binding with FcγRs (expressed on OPCs) (Nakahara et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Neuron-derived IgG Protects Neurons from Complement-dependent Cytotoxicity

Zhang¹,

Niu

et al. 2013

J Histochem Cytochem.

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Passive immunity of the nervous system has traditionally been thought to be predominantly due to the blood-brain barrier. This concept must now be revisited based on the existence of neuron-derived IgG. The conventional concept is that IgG is produced solely by mature B lymphocytes, but it has now been found to be synthesized by murine and human neurons. However, the function of this endogenous IgG is poorly understood. In this study, we confirm IgG production by rat cortical neurons at the protein and mRNA levels, with 69.0 ± 5.8% of cortical neurons IgG-positive. Injury to primary-culture neurons was induced by complement leading to increases in IgG production. Blockage of neuron-derived IgG resulted in more neuronal death and early apoptosis in the presence of complement. In addition, FcγRI was found in microglia and astrocytes. Expression of FcγR I in microglia was increased by exposure to neuron-derived IgG. Release of NO from microglia triggered by complement was attenuated by neuron-derived IgG, and this attenuation could be reversed by IgG neutralization. These data demonstrate that neuron-derived IgG is protective of neurons against injury induced by complement and microglial activation. IgG appears to play an important role in maintaining the stability of the nervous system.

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Monomeric IgG Is Neuroprotective via Enhancing Microglial Recycling Endocytosis and TNF-α

Cited by 46 publications

References 67 publications

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

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

TNF-α and Microglial Hormetic Involvement in Neurological Health & Migraine

Neuron-derived IgG Protects Neurons from Complement-dependent Cytotoxicity

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