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Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.

Ma-Krupa W, Jeon MS, Spoerl S, Tedder TF, Goronzy JJ, Weyand CM - J. Exp. Med. (2004)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

ABSTRACT
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.

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DCs in normal and inflamed temporal arteries. Temporal arteries were collected from diagnostic biopsies. Patients with granulomatous inflammatory infiltrates were categorized as having GCA. Patients were diagnosed with PMR if they had a typical clinical presentation but no vascular infiltrates. Normal temporal arteries were from patients who had neither PMR nor GCA. Paraffin-embedded arteries were stained with anti–S-100 (A), antifascin (B), or anti-CD11c Ab (C) to identify DCs. Frozen sections were stained with anti-CD83 Ab to assess DC activation (D–F). Normal temporal arteries contain a population of S-100+ (red), fascin+ (blue), and CD11c+ (brown) DCs positioned at the adventitia–media border (A–C). In noninflamed arteries, these DCs lack CD83 (D). Numerous CD83+ DCs (blue) participate in the granulomatous lesions in GCA (E). In arteries from patients with PMR, adventitial DCs have acquired the activation marker CD83 (F). Original magnification, 200 (D–F) and 400 (A–C).
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fig1: DCs in normal and inflamed temporal arteries. Temporal arteries were collected from diagnostic biopsies. Patients with granulomatous inflammatory infiltrates were categorized as having GCA. Patients were diagnosed with PMR if they had a typical clinical presentation but no vascular infiltrates. Normal temporal arteries were from patients who had neither PMR nor GCA. Paraffin-embedded arteries were stained with anti–S-100 (A), antifascin (B), or anti-CD11c Ab (C) to identify DCs. Frozen sections were stained with anti-CD83 Ab to assess DC activation (D–F). Normal temporal arteries contain a population of S-100+ (red), fascin+ (blue), and CD11c+ (brown) DCs positioned at the adventitia–media border (A–C). In noninflamed arteries, these DCs lack CD83 (D). Numerous CD83+ DCs (blue) participate in the granulomatous lesions in GCA (E). In arteries from patients with PMR, adventitial DCs have acquired the activation marker CD83 (F). Original magnification, 200 (D–F) and 400 (A–C).

Mentions: The adventitia functions as a support tissue for the vessel and provides the vasa vasorum and the capillary network that supply the wall structure with oxygen. In addition to the microvessels, the adventitia is composed of fibroblasts and it also contains a population of S-100+ cells (Fig. 1 A). These S-100+ cells express fascin and CD11c (Fig. 1, B and C) but not the monocyte/macrophage marker CD14, which is consistent with the phenotype of DCs. Adventitial DCs form a ring of extended dendrites at the outer edge of the external elastic lamina. They lack CD83 (Fig. 1 D), indicating that they are in a resting state (19). Each arterial cross section contains 20–25 DCs. This DC population is constant in number and morphology in patients who undergo temporal artery biopsy to rule out vasculitis and who have neither GCA nor PMR.


Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.

Ma-Krupa W, Jeon MS, Spoerl S, Tedder TF, Goronzy JJ, Weyand CM - J. Exp. Med. (2004)

DCs in normal and inflamed temporal arteries. Temporal arteries were collected from diagnostic biopsies. Patients with granulomatous inflammatory infiltrates were categorized as having GCA. Patients were diagnosed with PMR if they had a typical clinical presentation but no vascular infiltrates. Normal temporal arteries were from patients who had neither PMR nor GCA. Paraffin-embedded arteries were stained with anti–S-100 (A), antifascin (B), or anti-CD11c Ab (C) to identify DCs. Frozen sections were stained with anti-CD83 Ab to assess DC activation (D–F). Normal temporal arteries contain a population of S-100+ (red), fascin+ (blue), and CD11c+ (brown) DCs positioned at the adventitia–media border (A–C). In noninflamed arteries, these DCs lack CD83 (D). Numerous CD83+ DCs (blue) participate in the granulomatous lesions in GCA (E). In arteries from patients with PMR, adventitial DCs have acquired the activation marker CD83 (F). Original magnification, 200 (D–F) and 400 (A–C).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211768&req=5

fig1: DCs in normal and inflamed temporal arteries. Temporal arteries were collected from diagnostic biopsies. Patients with granulomatous inflammatory infiltrates were categorized as having GCA. Patients were diagnosed with PMR if they had a typical clinical presentation but no vascular infiltrates. Normal temporal arteries were from patients who had neither PMR nor GCA. Paraffin-embedded arteries were stained with anti–S-100 (A), antifascin (B), or anti-CD11c Ab (C) to identify DCs. Frozen sections were stained with anti-CD83 Ab to assess DC activation (D–F). Normal temporal arteries contain a population of S-100+ (red), fascin+ (blue), and CD11c+ (brown) DCs positioned at the adventitia–media border (A–C). In noninflamed arteries, these DCs lack CD83 (D). Numerous CD83+ DCs (blue) participate in the granulomatous lesions in GCA (E). In arteries from patients with PMR, adventitial DCs have acquired the activation marker CD83 (F). Original magnification, 200 (D–F) and 400 (A–C).
Mentions: The adventitia functions as a support tissue for the vessel and provides the vasa vasorum and the capillary network that supply the wall structure with oxygen. In addition to the microvessels, the adventitia is composed of fibroblasts and it also contains a population of S-100+ cells (Fig. 1 A). These S-100+ cells express fascin and CD11c (Fig. 1, B and C) but not the monocyte/macrophage marker CD14, which is consistent with the phenotype of DCs. Adventitial DCs form a ring of extended dendrites at the outer edge of the external elastic lamina. They lack CD83 (Fig. 1 D), indicating that they are in a resting state (19). Each arterial cross section contains 20–25 DCs. This DC population is constant in number and morphology in patients who undergo temporal artery biopsy to rule out vasculitis and who have neither GCA nor PMR.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus