Mast Cell Activation and Signaling in the Autoimmune Disease Bullous Pemphigoid Public Deposited

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  • March 22, 2019
Creator
  • Heimbach, Lisa A.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Bullous pemphigoid (BP) is an autoimmune skin blistering disorder primarily observed in the elderly. Autoantibodies directed against the hemidesmosomal protein BP180 trigger a pathological inflammatory response that causes separation of the epidermis from the underlying dermis. Complement, mast cells (MCs), and polymorphonuclear neutrophils (PMNs) are required for disease in experimental BP, an animal model that closely mimics the clinical, immunological and histological features of human BP. In this work, we investigated MC activation and signaling in experimental BP. MC degranulation occurs downstream of complement activation and the generation of complement component 5a (C5a) in experimental BP. We determined that C5a binds to the C5a receptor (C5aR) on MCs in neonatal mice given disease-inducing antibodies. C5a-C5aR interaction significantly increases phosphorylation of the intracellular signaling protein p38 mitogen-activated protein kinase (p38MAPK). Pharmacologically blocking p38MAPK activation protected mice from MC degranulation and clinical disease. Taken together, we demonstrated that the binding of C5a to C5aR on MCs activates the p38MAPK signaling pathway and leads to MC degranulation and skin blistering. Upon degranulation, MCs release bioactive compounds from their secretory granules, including tumor necrosis factor-alpha (TNF-α). Here, we report that MC-derived TNF-α is required for disease in experimental BP. Mice lacking TNF-α globally or in MCs alone fail to recruit sufficient numbers of PMNs to the skin and do not develop clinical blisters following injection with pathogenic anti-BP180 antibodies. C5aR-deficient mice are protected from blistering and do not exhibit elevated TNF-α levels or MC degranulation. TNF-α receptor 1 (TNFR1) expression on MCs is required for development of experimental BP, suggesting that TNF-α acts in an autocrine fashion on MCs. The findings described in this dissertation refine our understanding of the mechanisms of MC degranulation in experimental BP. MCs are activated by the binding of C5a to C5aR. C5a-C5aR interaction leads to activation of p38MAPK and MC degranulation. MC degranulation releases TNF-α, and TNF-α acts in an autocrine manner on MC TNFR1 to promote disease development. In addition to providing insight into the pathogenesis of BP, our data also suggests that C5a, p38MAPK, and TNF-α may be promising therapeutic targets for treatment of human disease.
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  • In Copyright
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology
Advisor
  • Liu, Zhi
Degree granting institution
  • University of North Carolina at Chapel Hill
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