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Iffland PH II_dissertation.pdf (12.35 MB)

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What doesn't kill you makes you stronger: the paradoxical effect of antibodies in epilepsy

Iffland, Philip H, II
http://rave.ohiolink.edu/etdc/view?acc_num=kent1436193807

Abstract Details

2015, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Many types of epilepsy, autoimmune or otherwise, are associated with the presence of autoantibodies against neuronal proteins. Paradoxically, antibodies (IVIg) have also been used to treat epilepsy. The goals of this research were twofold: 1) Determine the CNS location of antibodies in patients with non-autoimmune epilepsies and the targets of these antibodies; and 2) Examine the effects of endogenous and exogenous specific and non-specific antibodies in two status epilepticus (SE) models Immunohistochemistry and Western blotting were used to localize antibodies in patients with epilepsy, multiple sclerosis (MS) and arteriovenous malformation. Further analysis by ELISA, HEp-2 assay and immunoprecipitation revealed antibody targets. In mouse model experiments, lupus-prone or C57B6/J mice were injected with pilocarpine or kainic acid and monitored by EEG. Mice were treated with IV or IP injection of native or denatured IgGs, at time of or 12 hours before chemoconvulsant. Tissues were processed for immunohistochemistry and ELISA. Brain regions from patients with epilepsy contained extravasated IgGs. Intracellular antibodies were found in epilepsy but not in MS brain. In brain from patients with epilepsy, only neurons displayed nuclear IgGs. All subcellular fractions from brain resections of patients with epilepsy contained extravasated IgGs. In the nuclear IgG pool, anti-histone autoantibodies were identified by two independent methods. Serum analysis revealed anti-histone and anti-chromatin antibodies only in patients with epilepsy. In lupus-prone mice elevated serum IgGs favored post-SE survival. C57B6/J mice injected with native rat IgGs displayed a 40% reduction in pilocarpine-SE compared to control. IgGs extravasated in brains of untreated SE mice, but IgG-treated mice, with no pilocarpine-SE, experienced no parenchymal accumulation of IgGs. IgG leakage was observed in brain samples from KA treated mice and IgG treatment was largely ineffective. These results show intracellular IgGs in brain of patients with epilepsy are targeted to histones and chromatin. Further, injected non-specific IgGs have a seizure mitigating effect prophylactically or acutely. Intact IgGs prevent blood-brain barrier leakage and SE and may exert their effect on peripheral inflammation. As rat IgGs were used in these experiments, IVIg may exert its effect through a non-Fc receptor mechanism.
Derek Damron, Ph.D (Committee Chair)
Trine Jorgensen, Ph.D (Committee Member)
Gary Koski, Ph.D (Committee Member)
Ernest Freeman, Ph.D (Committee Member)
206 p.
Biology; Biomedical Research; Cellular Biology; Immunology; Medicine; Neurobiology; Neurosciences
antibodies; IgG; epilepsy; IVIg; antinuclear antibodies; blood-brain barrier disruption; autoantibodies; neuroprotection

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Citations

  • Iffland, II, P. H. (2015). What doesn't kill you makes you stronger: the paradoxical effect of antibodies in epilepsy [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1436193807

    APA Style (7th edition)

  • Iffland, II, Philip. What doesn't kill you makes you stronger: the paradoxical effect of antibodies in epilepsy. 2015. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1436193807.

    MLA Style (8th edition)

  • Iffland, II, Philip. "What doesn't kill you makes you stronger: the paradoxical effect of antibodies in epilepsy." Doctoral dissertation, Kent State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1436193807

    Chicago Manual of Style (17th edition)

kent1436193807
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This open access ETD is published by Kent State University and OhioLINK.