Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.
Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4(+) T cells are selectively activated in the adventitia of affected arteries. In human GCA artery-severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83(+) dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia-media border. Adoptive T cell transfer into temporal artery-SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II-matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.
Ma-Krupa
Wei
W
Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Jeon
Myung-Shin
MS
Spoerl
Silvia
S
Tedder
Thomas F
TF
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002678:Chimera; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D013700:Giant Cell Arteritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D017634:Self Tolerance; D014183:Transplantation, Heterologous
D017931:DNA Primers