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Superantigens, endothelial injury and vasculitis in the young

Brogan, Paul Anthony; (2003) Superantigens, endothelial injury and vasculitis in the young. Doctoral thesis (Ph.D), University of London. Green open access

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Abstract

Limited data exist suggesting a role for superantigens (SAgs) in the aetiopathogenesis of vasculitis syndromes in children and adults. The best evidence relates to Kawasaki Disease (the second commonest vasculitic syndrome of childhood), although this remains a controversial issue. Even fewer data exist examining how SAgs could cause endothelial and/or vascular injury. This thesis addressed these issues by examining peripheral blood T cell activation and T cell Vβ skewing in children with vasculitis. Secondly, an in vitro model was established to examine the hypothesis that the endothelial cell may operate as a competent SAg-presenting cell for T cells. Further evidence of endothelial injury in children with vasculitis was derived by examining circulating endothelial microparticles (EMP) in children with vasculitis at various stages of disease activity. Children with active vasculitis had higher CD4 and CDS peripheral blood T cell CD69 expression than those with inactive vasculitis and healthy controls, but not disease control children. No difference in CD25 expression in either the CD4 or CD8 T cell populations was observed between active and inactive vasculitis groups, however. There was a significantly increased variance of CD4 Vβ12, and Vβ17 and CD8 Vβ1 in the primary systemic vasculitis group as compared to control and disease controls. Moreover, 80% of the primary systemic vasculitis children had one or more CD4 Vβ expansions or deletions, as compared with 30% of controls and 37% of the disease controls (p<0.002). In the KD group, the mean % of CD4 Vβ12 T cells was higher than in controls or disease controls. Co-culture of purified T Cells and MHC class II+ HUVEC with SAg resulted in Vβ-restricted CD4 and CD8 CD69 upregulation. Additionally, there was CD4 and CD8 T Cell Vβ-restricted adherence to the HUVEC monolayer at 4 hours, which was partially abrogated by blockade of the integrin VLA-4, but not LFA-1. ICAM-1, E-selectin, and VCAM-1 expression were upregulated on the MHC class II+ HUVEC following exposure to SAg in the presence of T cells, and there was increased EMP release from the activated HUVEC. Plasma from patients with active vasculitis contained increased numbers of E-selectin and CD105 positive EMP compared with patients in remission, controls and disease controls. EMP correlated with clinical and laboratory indices of vasculitic disease activity, but there was overall a poor correlation between EMP and acute phase reactants in the disease controls. In conclusion, these data provide indirect evidence of superantigenic involvement in vasculitis syndromes of the young, and suggest that one possible mechanism of endothelial injury mediated by SAg could involve dual signaling between the endothelial cell (EC) and T cell, with EC activation and injury. These data also underscore the endothelium as both a target for injury in vasculitis, and as a potential amplifier of abherrant inflammatory responses, and suggest that circulating EMP may provide a window to the activated endothelium in vasculitis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Superantigens, endothelial injury and vasculitis in the young
Event: University of London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: This thesis has been digitised by ProQuest.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1312027
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