Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis.
BACKGROUND
Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen type V [col(V)] α1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Because specific induction of α1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis.


OBJECTIVE
To determine whether col(V) autoimmunity may be involved in the pathogenesis of atherosclerosis.


RESULTS
Here, we demonstrate Th17-dependent anti-col(V) immunity to be characteristic of atherosclerosis in human coronary artery disease (CAD) patients and in apolipoprotein E-null (ApoE(-/-)) atherosclerotic mice. Responses were α1(V)-specific in CAD with variable Th1 pathway involvement. In early atherosclerosis in ApoE(-/-) mice, anti-col(V) immunity was tempered by an interleukin (IL)-10-dependent mechanism. In support of a causal role for col(V) autoimmunity in the pathogenesis of atherosclerosis, col(V) sensitization of ApoE(-/-) mice on a regular chow diet overcame IL-10-mediated inhibition of col(V) autoimmunity, leading to increased atherosclerotic burden in these mice and local accumulation of IL-17-producing cells, particularly in the col(V)-rich adventitia subjacent to the atheromas.


CONCLUSIONS
These findings establish col(V) as an autoantigen in human CAD and show col(V) autoimmunity to be a consistent feature in atherosclerosis in humans and mice. Furthermore, data are consistent with a causative role for col(V) in the pathogenesis of atherosclerosis.
Dart
Melanie L
ML
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, 1300 University Ave., Madison, WI 53706, USA.
Jankowska-Gan
Ewa
E
Huang
Guorui
G
Roenneburg
Drew A
DA
Keller
Melissa R
MR
Torrealba
Jose R
JR
Rhoads
Aaron
A
Kim
Byoungjae
B
Bobadilla
Joseph L
JL
Haynes
Lynn D
LD
Wilkes
David S
DS
Burlingham
William J
WJ
Greenspan
Daniel S
DS
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002417:Cattle; D024062:Collagen Type V / Q000009:adverse effects / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001057:Apolipoproteins E; D024062:Collagen Type V; D020381:Interleukin-17
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