Basic Science
Abstract # 2127: Molecular Mechanisms of Target Tissue Susceptibility in Vasculitis-Comparative Genomics for Microbe-Sensing Receptors in Differenct Vascular Territories
Authors: Olga Pryshchep, Wei Ma-Krupa, Augusto Vaglio, Jörg J. Goronzy, Cornelia M. Weyand. Emory University School of Medicine, Atlanta, GA
Objective: The current classification system for the systemic vasculitides utilizes the size of the affected blood vessels as its primary criterion. The reasons why distinct vascular beds become inflamed in certain vasculitis syndromes remains unclear. Based on previous observations that human vascular beds express detectable levels of the innate immune system Toll-like receptors (TLRs), the authors hypothesized that differential expression of TLRs in different vascular territories might help explain the tropism seen in the systemic vasculitis syndromes.
Methods: mRNA derived from 6 atherosclerosis-free areas from unique vascular beds (temporal, carotid, subclavian, mesenteric, iliac, and thoracic aorta) was obtained from 23 individuals undergoing procedures for unrelated reasons. Quantitative PCR (qPCR) was performed with primer sets specific for 9 distinct TLRs. Dendritic cell (DC) distribution was assessed by immunohistochemistry (IHC), and functional relevance was determined by using the authors’ established artery grafting-to-SCID mouse system to assess the effects of specific TLR ligation (in this case TLR4 by LPS) on transferred human mononuclear cells.
Results: The authors showed that each arterial territory tested expressed a unique fingerprint of TLRs by qPCR. Certain related vascular beds shared TLR fingerprints (ie. the temporal/subclavian, and carotid/aorta). LPS-triggered TLR4 ligation activated resident DCs in all beds, and adoptively transferred mononuclear cells migrated to the implanted arteries, became activated, and secreted pro-inflammatory cytokines in temporal, subclavian, and carotid arteries predominantly.
Significance: This is an intriguing study that attempts to provide a molecular understanding for the well-known vascular bed tropism of the systemic vasculitis syndromes. The finding that only arteries derived from the great vessels of the neck were able to stimulate infiltrating immune cells is fascinating, and provides a further evidence to suggest that GCA might be initiated following an infectious trigger mediated by vascular-bed resident TLRs and DCs.