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KEY POINTS * Giant cell arteritis (GCA), the most frequent form of large-vessel vasculitis, occurs in a strictly defined tissue context and requires corruption of the immune-privileged

tissue niche of the arterial wall * Receptors and ligands from the Notch family facilitate information exchange between vascular stromal cells and immune cells, and are critically involved

in the development of vasculitis * The therapeutic potential of targeting the stromal compartment in vasculitis is currently unexplored * Granulomatous inflammation in GCA is characterized

by a cytokine cascade, in which the initiating signals are poorly defined, but the many effectors match those encountered in protective immune responses * A cytokine cluster involving the

IL-6–IL-17 axis is highly active in early and untreated disease, is rapidly suppressed by corticosteroids and is redundant for vasculitis * A cytokine cluster centring on the IL-12–IFN-γ

axis is more resistant to immunosuppression and reveals pathogenic similarities between allograft arteriosclerosis and GCA ABSTRACT Vasculitis of the medium and large arteries, most often

presenting as giant cell arteritis (GCA), is an infrequent, but potentially fatal, type of immune-mediated vascular disease. The site of the aberrant immune reaction, the mural layers of the

artery, is strictly defined by vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts, which engage in an interaction with T cells and macrophages to,

ultimately, cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of effector cytokines, all known as critical mediators in host-protective immunity, have been

identified in vasculitic lesions. Two dominant cytokine clusters—the IL-6–IL-17 axis and the IL-12–IFN-γ axis—have been linked to disease activity. These two clusters seem to serve different

roles in the vasculitic process. The IL-6–IL-17 cluster is highly responsive to standard corticosteroid therapy, whereas the IL-12–IFN-γ cluster is resistant to steroid-mediated

immunosuppression. The information exchange between vascular and immune cells and stabilization of the vasculitic process involves members of the Notch receptor and ligand family. Focusing

on elements in the tissue context of GCA, instead of broadly suppressing host immunity, might enable a more tailored therapeutic approach that avoids unwanted adverse effects of aggressive

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS LARGE-VESSEL VASCULITIS Article 06 January 2022 VASCULAR DAMAGE IN SYSTEMIC LUPUS ERYTHEMATOSUS Article 03 January 2024

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ACKNOWLEDGEMENTS The authors would like to acknowledge support from grants from the NIH (R01 EY011916, P01 HL058000, U19 AI057266 and U19 AI090019) and the Govenar Discovery Fund (C. M.

Weyand). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, CCSR Building Room 2225, Mail

Code 5166, 269 Campus Drive West, Stanford, 94305-5166, CA, USA Cornelia M. Weyand & Jörg J. Goronzy Authors * Cornelia M. Weyand View author publications You can also search for this

author inPubMed Google Scholar * Jörg J. Goronzy View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Both authors made equal contributions to

all aspects of this manuscript. CORRESPONDING AUTHOR Correspondence to Cornelia M. Weyand. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests.

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Weyand, C., Goronzy, J. Immune mechanisms in medium and large-vessel vasculitis. _Nat Rev Rheumatol_ 9, 731–740 (2013).

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