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• W2080500966 abstract "Weibel-Palade bodies within endothelial cells are secretory granules known to release von Willebrand Factor (VWF), P-selectin, chemokines, and other stored molecules following histamine exposure. Mice with a disrupted VWF gene (VWFKO) have endothelial cells that are deficient in Weibel-Palade bodies. These mice were used to evaluate the role of VWF and/or Weibel-Palade bodies in Bordetella pertussis toxin-induced hypersensitivity to histamine, a subphenotype of experimental allergic encephalomyelitis, the principal autoimmune model of multiple sclerosis. No significant differences in susceptibility to histamine between wild-type and VWFKO mice were detected after 3 days; however, histamine sensitivity persisted significantly longer in VWFKO mice. Correspondingly, encephalomyelitis onset was earlier, disease was more severe, and blood brain barrier (BBB) permeability was significantly increased in VWFKO mice, as compared with wild-type mice. Moreover, inflammation was selectively increased in the brains, but not spinal cords, of VWFKO mice as compared with wild-type mice. Early increases in BBB permeability in VWFKO mice were not due to increased encephalitogenic T-cell activity since BBB permeability did not differ in adjuvant-treated VWFKO mice as compared with littermates immunized with encephalitogenic peptide plus adjuvant. Taken together, these data indicate that VWF and/or Weibel-Palade bodies negatively regulate BBB permeability changes and autoimmune inflammatory lesion formation within the brain elicited by peripheral inflammatory stimuli. Weibel-Palade bodies within endothelial cells are secretory granules known to release von Willebrand Factor (VWF), P-selectin, chemokines, and other stored molecules following histamine exposure. Mice with a disrupted VWF gene (VWFKO) have endothelial cells that are deficient in Weibel-Palade bodies. These mice were used to evaluate the role of VWF and/or Weibel-Palade bodies in Bordetella pertussis toxin-induced hypersensitivity to histamine, a subphenotype of experimental allergic encephalomyelitis, the principal autoimmune model of multiple sclerosis. No significant differences in susceptibility to histamine between wild-type and VWFKO mice were detected after 3 days; however, histamine sensitivity persisted significantly longer in VWFKO mice. Correspondingly, encephalomyelitis onset was earlier, disease was more severe, and blood brain barrier (BBB) permeability was significantly increased in VWFKO mice, as compared with wild-type mice. Moreover, inflammation was selectively increased in the brains, but not spinal cords, of VWFKO mice as compared with wild-type mice. Early increases in BBB permeability in VWFKO mice were not due to increased encephalitogenic T-cell activity since BBB permeability did not differ in adjuvant-treated VWFKO mice as compared with littermates immunized with encephalitogenic peptide plus adjuvant. Taken together, these data indicate that VWF and/or Weibel-Palade bodies negatively regulate BBB permeability changes and autoimmune inflammatory lesion formation within the brain elicited by peripheral inflammatory stimuli. The blood-brain barrier (BBB) is a physical and metabolic barrier between the central nervous system (CNS) and peripheral circulation that is critical for regulating and protecting the CNS microenvironment.1Zlokovic BV The blood-brain barrier in health and chronic neurodegenerative disorders.Neuron. 2008; 57: 178-201Abstract Full Text Full Text PDF PubMed Scopus (2375) Google Scholar Tight junctions formed by interactions between transmembrane proteins (claudins, occludin, and junction adhesion molecules) on adjacent cerebral microvascular endothelial cells (ECs) form the barrier, which, together with pericytes surrounded by basal lamina, astrocytic end-feet, and perivascular interneurons, comprise the neurovascular unit that is essential for the health and function of the CNS. Disruption of tight junctions leads to increased BBB permeability that is well documented in a variety of CNS diseases including multiple sclerosis (MS), an inflammatory demyelinating disorder of CNS of unknown etiology.1Zlokovic BV The blood-brain barrier in health and chronic neurodegenerative disorders.Neuron. 2008; 57: 178-201Abstract Full Text Full Text PDF PubMed Scopus (2375) Google Scholar Indeed, both demyelination and plaque formation are more pronounced in areas surrounding small vessels in MS patients.2Correale J Villa A The blood-brain-barrier in multiple sclerosis: functional roles and therapeutic targeting.Autoimmunity. 2007; 40: 148-160Crossref PubMed Scopus (89) Google Scholar Dysregulation of the BBB and transendothelial migration of activated leukocytes across the BBB into the parenchymal perivascular space are essential and critical steps in triggering CNS inflammation and subsequent tissue injury.2Correale J Villa A The blood-brain-barrier in multiple sclerosis: functional roles and therapeutic targeting.Autoimmunity. 2007; 40: 148-160Crossref PubMed Scopus (89) Google Scholar Therefore, understanding the mechanisms associated with BBB permeability changes leading to increased CNS infiltration may provide for newer therapeutic strategies to control disease progression. Experimental allergic encephalomyelitis (EAE) is the principal autoimmune model of MS.3Steinman L Zamvil SS How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis.Ann Neurol. 2006; 60: 12-21Crossref PubMed Scopus (417) Google Scholar Pertussis toxin (PTX) is used as an ancillary adjuvant in the induction of EAE.4Munoz JJ Arai H Bergman RK Sadowski PL Biological activities of crystalline pertussigen from Bordetella pertussis.Infect Immun. 1981; 33: 820-826Crossref PubMed Google Scholar Intoxication with PTX elicits an array of physiological responses in vivo, including increased BBB permeability and sensitization of the vascular endothelium to vasoactive agents such as histamine (HA).5Locht C Molecular aspects of Bordetella pertussis pathogenesis.Int Microbiol. 1999; 2: 137-144PubMed Google Scholar, 6Munoz JJ Sekura RD Moss J Vaughn M Biological activities of pertussigen (pertussis toxin). Academic Press, Orlando FL1985: 1-18Google Scholar Inbred strains of mice differ in susceptibility to challenge with vasoactive agents following sensitization with PTX in that genetically susceptible strains succumb to hypotensive and hypovolemic shock, while resistant strains do not.7Wardlaw AC Inheritance of responsiveness to pertussis HSF in mice.Int Arch Allergy Appl Immunol. 1970; 38: 573-589Crossref PubMed Scopus (26) Google Scholar Additionally, the genetic control of susceptibility to lethal shock is agent specific.8Gao JF Call SB Fillmore PD Watanabe T Meeker ND Teuscher C Analysis of the role of Bphs/Hrh1 in the genetic control of responsiveness to pertussis toxin.Infect Immun. 2003; 71: 1281-1287Crossref PubMed Scopus (11) Google Scholar For example, PTX-induced vascular endothelial sensitization, controlled by Bordetella pertussis induced HA sensitization (Bphs), is detected by HA challenge but not by serotonin challenge. Bphs is an autosomal dominant locus that we recently identified as the histamine H1 receptor (Hrh1/H1R).9Ma RZ Gao J Meeker ND Fillmore PD Tung KS Watanabe T Zachary JF Offner H Blankenhorn EP Teuscher C Identification of Bphs, an autoimmune disease locus, as histamine receptor H1.Science. 2002; 297: 620-623Crossref PubMed Scopus (137) Google Scholar Importantly, susceptibility to EAE is also controlled by Bphs/Hrh1,9Ma RZ Gao J Meeker ND Fillmore PD Tung KS Watanabe T Zachary JF Offner H Blankenhorn EP Teuscher C Identification of Bphs, an autoimmune disease locus, as histamine receptor H1.Science. 2002; 297: 620-623Crossref PubMed Scopus (137) Google Scholar, 10Linthicum DS Frelinger JA Acute autoimmune encephalomyelitis in mice. II. Susceptibility is controlled by the combination of H-2 and histamine sensitization genes.J Exp Med. 1982; 156: 31-40Crossref PubMed Scopus (144) Google Scholar underscoring the role of genetic factors in regulating BBB permeability and susceptibility to inflammatory demyelinating diseases of the CNS. The mechanism whereby PTX sensitizes the vascular endothelium to HA is unknown, but it is consistent with a two-step process: an induction phase, characterized by a 2- to 3-day latent period following intoxication, and an effector phase, manifest by rapid onset of lethal shock that usually occurs within 30 minutes of HA challenge.11Munoz J Bergman RK Histamine-sensitizing factors from microbial agents, with special reference to Bordetella pertussis.Bacteriol Rev. 1968; 32: 103-126Crossref PubMed Google Scholar, 4Munoz JJ Arai H Bergman RK Sadowski PL Biological activities of crystalline pertussigen from Bordetella pertussis.Infect Immun. 1981; 33: 820-826Crossref PubMed Google Scholar Bphs is also characterized by a protracted period of sensitivity that persists upwards of 30 days.4Munoz JJ Arai H Bergman RK Sadowski PL Biological activities of crystalline pertussigen from Bordetella pertussis.Infect Immun. 1981; 33: 820-826Crossref PubMed Google Scholar The fact that sensitization of the vascular endothelium continues well beyond the likely half-life of the toxin in vivo suggests that the induction phase may be associated with the synthesis and storage of additional vasoactive factors within ECs that are released by exposure to HA during the effector phase. In this regard, it is known that following exposure to inflammatory mediators, vasoactive factors such as KC (IL-8 homologue), eotaxin-3, von Willebrand Factor (VWF), P-selectin, CD63/lamp3, angiopoietin 2, endothelin-1, endothelin converting enzyme, tissue-type plasminogen activator, factor XIIa, and/or α1,3-fucosyltransferase VI can be stored in EC Weibel-Palade bodies (WPBs),12Rondaij MG Bierings R Kragt A van Mourik JA Voorberg J Dynamics and plasticity of Weibel-Palade bodies in endothelial cells.Arterioscler Thromb Vasc Biol. 2006; 26: 1002-1007Crossref PubMed Scopus (268) Google Scholar and that HA is a secretagogue for the release of these agents.13Hattori R Hamilton KK Fugate RD McEver RP Sims PJ Stimulated secretion of endothelial von Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140.J Biol Chem. 1989; 264: 7768-7771Abstract Full Text PDF PubMed Google Scholar Under this hypothetical two-step model, lethal shock would be caused by (1) the antecedent induction phase due to PTX exposure, and (2) the direct vasodilatory activity of HA combined with the effects of the stored products released from WPBs. In the absence of exposure to PTX, the ECs must be able to compensate for the effects of subsequently administered HA because most mice do not succumb following HA challenge alone. In contrast, PTX-exposed ECs are not able to compensate for the increase in synergistic second messenger signaling arising from exposure to both HA and PTX-induced vasoactive factors stored in WPBs. In this study, mice with a disrupted VWF gene (VWFKO) and a consequent deficiency in WPBs14Denis C Methia N Frenette PS Rayburn H Ullman-Cullere M Hynes RO Wagner DD A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis.Proc Natl Acad Sci USA. 1998; 95: 9524-9529Crossref PubMed Scopus (434) Google Scholar were used to directly test this hypothesis, and to evaluate the role of VWF and/or WPBs in regulating BBB permeability and susceptibility to EAE. We report that, contrary to this model, VWF and/or WPBs suppress both Bphs and adjuvant-induced alterations in BBB function associated with actively induced EAE. B6.129S2-Vwftm1Wgr (VWFKO) mice14Denis C Methia N Frenette PS Rayburn H Ullman-Cullere M Hynes RO Wagner DD A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis.Proc Natl Acad Sci USA. 1998; 95: 9524-9529Crossref PubMed Scopus (434) Google Scholar were maintained in the vivarium of the Given Medical Building at the University of Vermont (Burlington, VT). Wild-type (WT) C57BL/6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Animals were fed RMH 3000 Lab Diet Rodent Chow (Ralston-Purina, St. Louis, MO) and tap water ad libitum and maintained in accordance with the Animal Welfare Act and the Public Health Service Policy on the Humane Care and Use of Laboratory Animals. The experimental procedures used in this study were approved by the Animal Care and Use Committee of the University of Vermont. Mice were injected intravenously (i.v.) with purified PTX (List Biological Laboratories, Inc., Campbell, CA) in 0.025 M Tris buffer containing 0.5 M NaCl and 0.017% Triton X-100, pH 7.6. Control animals received carrier. HA sensitivity was determined by the i.v. injection of varying amounts of HA (mg/kg dry weight free base) (Sigma, St. Louis, MO) suspended in PBS. Deaths were recorded at 30 minutes postchallenge. The results are expressed as the number of deaths per the number of animals studied. Mice were immunized for the active induction of EAE and draining lymph nodes were harvested 10 days later. Single-cell suspensions were prepared and 5 × 105 draining lymph node cells/well were plated on standard 96-well flat-bottom tissue culture plates, for 72 hours at 37°C and 7% CO2 with and without myelin oligodendrocyte glycoprotein peptide35–55 (MOG35–55) (Beckman Institute, Paolo Alto, CA) and in the presence of 1.0 μCi 3H-thymidine during the last 18 hours. Cells were harvested onto glass fiber filters, and thymidine uptake was determined by liquid scintillation. Mice were immunized for the active induction of EAE and spleens were harvested 10 days later. Single-cell suspensions were prepared and 4 × 106 cells/ml were cultured in 24-well culture plates in media containing 50 μg/ml MOG35–55. Cell culture supernatants were recovered after 72 hours and frozen at −70°C until assayed. Interleukin (IL)-12, IL-10, IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1 (MCP-1), and interferon-γ were detected by cytometric bead assay (Becton-Dickinson Bioscience, San Jose, CA). Fifty μl of cell culture supernatant was mixed with 50 μl of the mixed capture beads and 50 μl of the mouse phycoerythrin detection reagent. The tubes were incubated at room temperature for 2 hours in the dark, followed by a wash step. The samples were then resuspended in 400 μl of wash buffer before acquisition on the FACScan (Becton-Dickinson BioScience, San Jose, CA). The data were analyzed using cytometric bead assay software. Standard curves were generated for each cytokine using the mixed bead standard provided in the kit, and the concentration of cytokine in the cell supernatant was determined by interpolation from the appropriate standard curve. For real-time RT-PCR analysis, total RNA was isolated using the RNeasy minikit protocol (Qiagen, Valencia, CA) and then converted to cDNA using oligo(dT), random hexamers, and Superscript RT II enzyme (Invitrogen, Grand Island, NY). Message levels were quantified using the ABI 7000 Real-Time PCR System (Applied Biosystems, Foster City, CA). Amplification was performed in a total volume of 25 μl for 40 cycles and products were detected using SYBR Green I dye (Molecular Probes, Eugene, OR). Samples were run in triplicate and relative expression level was determined by normalizing to L32 with the results presented as relative abundance. Primer sequences used have been described before.15Teuscher C Subramanian M Noubade R Gao JF Offner H Zachary JF Blankenhorn EP Central histamine H3 receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS.Proc Natl Acad Sci USA. 2007; 104: 10146-10151Crossref PubMed Scopus (88) Google Scholar EAE was induced as previously described.16Teuscher C Noubade R Spach K McElvany B Bunn JY Fillmore PD Zachary JF Blankenhorn EP Evidence that the Y chromosome influences autoimmune disease in male and female mice.Proc Natl Acad Sci USA. 2006; 103: 8024-8029Crossref PubMed Scopus (80) Google Scholar Briefly, mice were injected subcutaneously in the flanks and neck with 0.1 ml of an emulsion containing 200 μg of MOG35–55 in saline and an equal volume of complete Freund's adjuvant containing 200 μg of Mycobacterium tuberculosis H37RA (Difco Laboratories, Detroit, MI). On the day of immunization, each mouse received 200 ng of PTX by i.v. injection. The mice were assessed daily for clinical signs of EAE using the following scale: 0, normal; 1, limp tail or mild hind limb weakness; 2, moderate hind limb weakness or mild ataxia; 3, moderately severe hind limb weakness; 4, severe hind limb weakness or mild forelimb weakness or moderate ataxia; 5, paraplegia with no more than moderate forelimb weakness; 6, paraplegia with severe forelimb weakness or severe ataxia or moribund condition. Brains and spinal cords were dissected from calvaria and vertebral columns, respectively, and fixed by immersion in 10% phosphate-buffered formalin (pH 7.2). Following adequate fixation, brains and spinal cords were trimmed and representative transverse section embedded in paraffin, sectioned at 5 μm, and mounted on glass slides. Sections were stained with H&E for routine evaluation and Luxol fast blue-periodic acid Schiff for demyelination. Sections from representative areas of the brain and spinal cord were scored in a semiquantitative fashion for the various histopathological parameters as previously described.15Teuscher C Subramanian M Noubade R Gao JF Offner H Zachary JF Blankenhorn EP Central histamine H3 receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS.Proc Natl Acad Sci USA. 2007; 104: 10146-10151Crossref PubMed Scopus (88) Google Scholar, 16Teuscher C Noubade R Spach K McElvany B Bunn JY Fillmore PD Zachary JF Blankenhorn EP Evidence that the Y chromosome influences autoimmune disease in male and female mice.Proc Natl Acad Sci USA. 2006; 103: 8024-8029Crossref PubMed Scopus (80) Google Scholar, 17Butterfield RJ Blankenhorn EP Roper RJ Zachary JF Doerge RW Sudweeks J Rose J Teuscher C Genetic analysis of disease subtypes and sexual dimorphisms in mouse experimental allergic encephalomyelitis (EAE): relapsing/remitting and monophasic remitting/nonrelapsing EAE are immunogenetically distinct.J Immunol. 1999; 162: 3096-3102PubMed Google Scholar Briefly, EAE pathology was scored for the overall severity of the lesions observed, the extent and degree of demyelination and tissue injury (swollen axon sheathes, swollen axons, and reactive gliosis), severity of the acute inflammatory response such as neutrophil infiltration, and the severity of the chronic inflammatory response (lymphocytes/monocytes). BBB permeability was assessed as previously described.18Tang T Frenette PS Hynes RO Wagner DD Mayadas TN Cytokine-induced meningitis is dramatically attenuated in mice deficient in endothelial selectins.J Clin Invest. 1996; 97: 2485-2490Crossref PubMed Scopus (121) Google Scholar Briefly, a 50 μg/g dose of fluorescein isothiocyanate-labeled bovine serum albumin (Sigma, St. Louis, MO) was injected i.v. into WT and VWFKO mice on day 8, 10, or 12 post immunization with CFA+PTX+MOG35–55, CFA+PTX. Cerebrospinal fluid and blood were collected after 4 hours. Both cerebrospinal fluid and plasma samples, prepared by centrifugation at 3000 rpm for 15 minutes, were diluted in PBS, and the fluorescence intensity was measured with a microplate fluorescence reader (Flx-800-I, Bio-Tek Instruments Inc, Winooski, VT) using the software KC-4, with an excitation wavelength of 485 nm and an emission wavelength of 528 nm. The BBB permeability index is expressed as the ratio of the fluorescence intensity of the CSF divided by the fluorescence intensity of the plasma. Statistical analyses were performed using GraphPad Prism 4 software (GraphPad software Inc, San Diego, CA). Significance of difference was assessed by two-way analysis of variance and/or regression analysis. For all analyses P ≤ 0.05 was considered significant. The role of VWF and/or WPBs in Bphs was evaluated by i.v. sensitization of WT and VWFKO mice with 200 ng PTX on day 0. Three days later, HA sensitivity was assessed in a dose-response fashion by i.v. challenge with HA and deaths were recorded at 30 minutes. A significant difference in the LD50 values between the two strains was not detected (WT = 1.65 ± 0.05 mg/kg versus VWFKO = 1.41 ± 0.08 mg/kg; F = 0.55, P = 0.46), indicating that neither VWF nor WPBs are required for Bphs susceptibility. Given the role of WPBs in vascular function, we nevertheless assessed their effect on the persistence of HA sensitivity. As compared with WT mice, HA sensitivity persisted longer in VWFKO mice at all challenge doses studied (F = 38.25; P < 0.0001) (Figure 1). The half-life of sensitization was 64.8 days in VWFKO mice compared 34.4 days in WT mice at 100 mg/kg HA challenge. Similarly, the sensitization half-lives were 66.0 and 63.3 days in VWFKO mice at 50 mg/kg and 25 mg/kg of HA, respectively while the corresponding sensitization half-lives in WT mice were 34.2 and 30.7 days. Taken together, these data demonstrate that VWF and/or WPBs ordinarily act to shorten the longevity of HA sensitivity elicited by in vivo intoxication with PTX. Because VWFKO mice exhibited significantly prolonged sensitivity to HA, and Bphs is an EAE susceptibility gene,9Ma RZ Gao J Meeker ND Fillmore PD Tung KS Watanabe T Zachary JF Offner H Blankenhorn EP Teuscher C Identification of Bphs, an autoimmune disease locus, as histamine receptor H1.Science. 2002; 297: 620-623Crossref PubMed Scopus (137) Google Scholar we studied the role of VWF and/or WPBs in regulating EAE induced by immunization with MOG35–55+CFA+PTX. As compared with WT mice, VWFKO mice developed significantly more severe clinical signs of EAE (Figure 2). Clinical signs of EAE in VWFKO mice were notably enhanced during the acute-early phase (D7 through D18 postimmunization) as compared with the chronic late-phase of the disease (day 20 to 30).19Polanczyk M Yellayi S Zamora A Subramanian S Tovey M Vandenbark AA Offner H Zachary JF Fillmore PD Blankenhorn EP Gustafsson JA Teuscher C Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice.Am J Pathol. 2004; 164: 1915-1924Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar The mean day of disease onset in VWFKO mice was 14.1 ± 2.0 vs. 16.4 ± 3.2 (P = 0.01) in WT mice. The acute-early phase cumulative disease score in VWFKO mice was 22.6 ± 11.1 vs. 13.3 ± 11.9 (P = 0.008) in WT mice. Histological analysis of CNS samples obtained during the acute-early phase of the disease revealed that VWFKO mice exhibited significantly greater pathology in the brain than did WT mice (Figure 3, A and B). This was reflected in VWFKO mice having a higher average overall pathology index with significantly greater lesion scores, more severe demyelination, more suppuration, and more extensive mononuclear cell infiltrates (Figure 4A). In contrast, however, no difference in the overall severity of the lesions between VWFKO and WT mice was observed in the spinal cord (Figure 3, C and D; Figure 4B). These results demonstrate that the absence of VWF and/or WPB selectively promotes lesion formation in the brain, compared to the spinal cord-dominant disease seen in mice with intact VWF and WPBs.Figure 4Quantification of lesion severity in WT and VWFKO mice. The histopathological lesions were scored in MOG35–55+CFA+PTX immunized WT (n = 18) and VWFKO (n = 25) mice in a semiquantitative manner as described in Material and Methods, which revealed that the lesions in the brains (A) but not in spinal cords (B) of VWFKO mice are more severe compared to WT controls. Significance of differences was determined using the Student's t-test.View Large Image Figure ViewerDownload Hi-res image Download (PPT) We examined a number of T cell parameters in WT and VWFKO mice following sensitization with MOG35–55+CFA+ PTX to evaluate the encephalitogenic T cell response elicited in each strain. No difference in the proliferative response of spleen cells to MOG35–55 at day 10 p.i. was observed between WT and VWFKO mice (Figure 5A). Similarly, no significant differences in cytokine and chemokine expression following ex vivo restimulation with MOG35–55, were detected between WT and VWFKO animals (Figure 5, B and C). Taken together, these results indicate that the more severe acute-early phase disease seen in VWFKO mice is unlikely to be due to a direct effect of the absence of VWF and/or WPBs on T cell effector responses. To delineate the mechanisms underlying the more severe acute-early phase EAE in VWFKO mice, we analyzed EC function by measuring BBB permeability. A BBB permeability index (BBB-PI) was determined by measuring the traverse of systemically injected fluorescein isothiocyanate-labeled bovine serum albumin into the cerebrospinal fluid of EAE-induced mice at 8, 10, and 12 days p.i. (Figure 6). BBB-PIs were not significantly different between unimmunized WT and VWFKO mice; however, BBB-PIs were significantly elevated in both mouse strains (P = 0.01 for WT and P < 0.0001 for VWFKO) following immunization with MOG35–55+CFA+PTX. Moreover, the test of the main effect of group (mouse strain) showed a significant difference (P = 0.02) between the two strains, with the BBB-PI being greater in VWFKO mice compared to WT mice. The significant difference in clinical signs and brain pathology between WT and VWFKO mice during the acute-early phase of the disease, despite the absence of detectable differences in encephalitogenic T cell effector responses, point to a potential role for VWF and/or WPBs in regulating the interface between the circulation and the brain. We therefore compared the integrity of the BBB in WT and VWFKO mice at various time points after injection with MOG35–55+CFA+PTX or CFA+PTX. Immunization with CFA+PTX alone lead to increased BBB permeability in WT mice (Figure 7A) to an extent that was not different from that seen following immunization with MOG35–55+CFA+PTX (P = 0.45). The change in BBB permeability over time was also not significant in WT mice (P = 0.08). Similarly, immunization with CFA+PTX alone significantly increased the BBB permeability in VWFKO mice but again, there was no difference in the BBB-PIs between the animals immunized with or without the encephalitogen (P = 0.27) (Figure 7B). This indicates that in both WT and VWFKO mice, antigen-specific encephalitogenic T cells are not responsible for eliciting increased BBB permeability across the time points studied. Because the BBB-PIs between the animals immunized with or without MOG35–55 were not different, they were pooled and reanalyzed. The results revealed that the BBB-PI in VWFKO mice was significantly greater than the BBB-PI in WT mice (P = 0.0005) (Figure 7C) when CFA and PTX are used as adjuvants, and that this difference is encephalitogen-independent. These data indicate that VWF and/or WPBs protect against the vascular permeability changes induced by these inflammatory agents. In this study we show that the absence of VWF and/or WPBs leads to increased BBB permeability and, in appropriately immunized mice, concomitantly more severe EAE. The disruption of BBB integrity is due to adjuvants alone; and although the mechanism(s) by which CFA and PTX act to increase BBB permeability is unknown, these processes are independent of encephalitogenic T cell responses. This is in agreement with previous studies looking at the effects of inflammatory pain elicited by formalin, CFA and λ-carrageenan on BBB permeability.20Hawkins BT Davis TP The blood-brain barrier/neurovascular unit in health and disease.Pharmacol Rev. 2005; 57: 173-185Crossref PubMed Scopus (2014) Google Scholar, 21Brooks TA Ocheltree SM Seelbach MJ Charles RA Nametz N Egleton RD Davis TP Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain.Brain Res. 2006; 1120: 172-182Crossref PubMed Scopus (43) Google Scholar BBB permeability changes elicited by these stimuli were associated with unique alterations in the temporal expression of tight junctional proteins as well as disruption of the interaction between tight junctional complexes and the cytoskeleton. It is unclear what the mechanism(s) for tight junctional alterations following peripheral inflammation might be, but both CFA and PTX are known to lead to increased levels of IL-1β, tumor necrosis factor-α, and/or IL-6 within the periphery and CNS rapidly after exposure.22Loscher CE Donnelly S Mills KH Lynch MA Interleukin-1beta-dependent changes in the hippocampus following parenteral immunization with a whole cell pertussis vaccine.J Neuroimmunol. 2000; 111: 68-76Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 23Loscher CE Donnelly S Lynch MA Mills KH Induction of inflammatory cytokines in the brain following respiratory infection with Bordetella pertussis.J Neuroimmunol. 2000; 102: 172-181Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 24Donnelly S Loscher CE Lynch MA Mills KH Whole-cell but not acellular pertussis vaccines induce convulsive activity in mice: evidence of a role for toxin-induced interleukin-1beta in a new murine model for analysis of neuronal side effects of vaccination.Infect Immun. 2001; 69: 4217-4223Crossref PubMed Scopus (48) Google Scholar, 25Armstrong ME Loscher CE Lynch MA Mills KH IL-1beta-dependent neurological effects of the whole cell pertussis vaccine: a role for IL-1-associated signalling components in vaccine reactogenicity.J Neuroimmunol. 2003; 136: 25-33Abstract Full Text Full Text" @default.
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• W2080500966 title "Von-Willebrand Factor Influences Blood Brain Barrier Permeability and Brain Inflammation in Experimental Allergic Encephalomyelitis" @default.
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