The project has investigated innate and adaptive immune responses in medium and large vessel vasculitis. Giant cell arteritis, a granulomatous vasculitis, has served as a disease model. The progress made in this project, however, has had far-reaching implications, not only for vasculitides, but also on evolving concepts of inflammation in atherosclerosis.
Due to the vital function of blood vessels and their nonregenerative nature, vascular inflammation poses an immediate threat to the host, particularly when targeting large arteries. In giant cell arteritis, inflammatory destruction leads to blindness, stroke, and aortic aneurysm. In the case of atherosclerotic disease, the inflammation is more localized, but inflammatory destruction of the atherosclerotic plaque causes myocardial infarction and stroke. The ultimate goal of this project was to understand how inflammation in human arteries is initiated and regulated. A critical element of this study was the discovery of dendritic cells (DC) that are indigenous to human arteries and function as gatekeepers in protecting arteries from immune attack.
In summary, studies supported by the project have been crucial in deciphering the immunoregulatory function of human arteries. The work has established that human blood vessels have sensing function for microbial infection. Exposure to pathogen-derived ligands initiates activation of adventitia-positioned DCs that are located closely to the vasa vasorum tree and obviously screen for circulating indicators of danger. Ligands for several Toll-like receptors (TLRs), including TLR3, TLR4, and TLR5, can all induce vascular DC activation. Remarkably, each ligand initiates a distinct DC activation program, and the instructions for T cells are unique for each of the stimulating patterns. Depending on the precise instruction provided by the vascular DC, T cells display tissue-invasive character or are arrested in the outer layer of the vessel wall. TLR4 stimulation emerges as a signal that most closely mimics conditions of vasculitis, raising the intriguing question of whether TLR4-binding molecules have a direct role in causing giant cell arteritis.