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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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Functional characteristics of arterial wall DCs in normal arteries. Temporal arteries were collected from patients with neither GCA nor PMR. Tissue extracts from fresh shock-frozen samples were analyzed for TLR2- and TLR4-specific sequences by PCR. All negative arteries (marked as 1–6) contained mRNA transcripts for TRL2 and TLR4 (A). To test the responsiveness of arterial DCs to triggering with blood-born TNF-α or TLR ligands, we implanted pieces of arteries into SCID mice. 7–10 d after implantation, the SCID mouse chimeras were injected with 2 μg i.v. TNF-α, 10 μg i.v. LPS, or 100 μl i.p. CFA, and the arterial grafts were harvested 48 h later. Tissue extracts from the explanted grafts were analyzed for the mRNA transcripts of β-actin, CD83, IL-18, and the chemokines CCL18, CCL19, and CCL21. After stimulation with blood-born triggers, arterial wall DCs expressed CD83+ and began to produce an array of chemokines. The effect of TNF-α was limited to the induction of CCL21, whereas LPS induced the full spectrum of chemokines. One experiment representative of three is shown (B). Immunohistochemistry confirmed that arterial DCs from LPS-treated (left), but not control (right), arteries expressed CD83 (blue) and produced CCL21 (red) (C). Original magnification, 200 (except LPS-treated CD83 and CCL21 images, which were 600×). P, positive PCR control; N, untreated mouse control; and W, negative PCR control.
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fig4: Functional characteristics of arterial wall DCs in normal arteries. Temporal arteries were collected from patients with neither GCA nor PMR. Tissue extracts from fresh shock-frozen samples were analyzed for TLR2- and TLR4-specific sequences by PCR. All negative arteries (marked as 1–6) contained mRNA transcripts for TRL2 and TLR4 (A). To test the responsiveness of arterial DCs to triggering with blood-born TNF-α or TLR ligands, we implanted pieces of arteries into SCID mice. 7–10 d after implantation, the SCID mouse chimeras were injected with 2 μg i.v. TNF-α, 10 μg i.v. LPS, or 100 μl i.p. CFA, and the arterial grafts were harvested 48 h later. Tissue extracts from the explanted grafts were analyzed for the mRNA transcripts of β-actin, CD83, IL-18, and the chemokines CCL18, CCL19, and CCL21. After stimulation with blood-born triggers, arterial wall DCs expressed CD83+ and began to produce an array of chemokines. The effect of TNF-α was limited to the induction of CCL21, whereas LPS induced the full spectrum of chemokines. One experiment representative of three is shown (B). Immunohistochemistry confirmed that arterial DCs from LPS-treated (left), but not control (right), arteries expressed CD83 (blue) and produced CCL21 (red) (C). Original magnification, 200 (except LPS-treated CD83 and CCL21 images, which were 600×). P, positive PCR control; N, untreated mouse control; and W, negative PCR control.

Mentions: Considering the critical role of DCs in the vasculitic response, we wanted to explore whether DCs indigenous to the adventitia that are physiologically in a resting state could be stimulated to differentiate in vivo. DCs respond to their microenvironment through a number of different receptors, of which TLRs play an important role (25). To determine the TLR profile expressed by adventitial DCs under normal conditions, we amplified by PCR tissue extracts from normal temporal arteries with primers specific for TLR2 and TLR4. TLR2- and TLR4-specific sequences were present in all normal temporal arteries (Fig. 4 A). To examine DC activation in vivo, temporal arteries from patients who had neither GCA nor PMR were engrafted into SCID mice, and the chimeras were injected with a panel of mediators known to activate DCs. The temporal arteries were explanted and analyzed for transcripts typically produced by activated DCs.


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)

Functional characteristics of arterial wall DCs in normal arteries. Temporal arteries were collected from patients with neither GCA nor PMR. Tissue extracts from fresh shock-frozen samples were analyzed for TLR2- and TLR4-specific sequences by PCR. All negative arteries (marked as 1–6) contained mRNA transcripts for TRL2 and TLR4 (A). To test the responsiveness of arterial DCs to triggering with blood-born TNF-α or TLR ligands, we implanted pieces of arteries into SCID mice. 7–10 d after implantation, the SCID mouse chimeras were injected with 2 μg i.v. TNF-α, 10 μg i.v. LPS, or 100 μl i.p. CFA, and the arterial grafts were harvested 48 h later. Tissue extracts from the explanted grafts were analyzed for the mRNA transcripts of β-actin, CD83, IL-18, and the chemokines CCL18, CCL19, and CCL21. After stimulation with blood-born triggers, arterial wall DCs expressed CD83+ and began to produce an array of chemokines. The effect of TNF-α was limited to the induction of CCL21, whereas LPS induced the full spectrum of chemokines. One experiment representative of three is shown (B). Immunohistochemistry confirmed that arterial DCs from LPS-treated (left), but not control (right), arteries expressed CD83 (blue) and produced CCL21 (red) (C). Original magnification, 200 (except LPS-treated CD83 and CCL21 images, which were 600×). P, positive PCR control; N, untreated mouse control; and W, negative PCR control.
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fig4: Functional characteristics of arterial wall DCs in normal arteries. Temporal arteries were collected from patients with neither GCA nor PMR. Tissue extracts from fresh shock-frozen samples were analyzed for TLR2- and TLR4-specific sequences by PCR. All negative arteries (marked as 1–6) contained mRNA transcripts for TRL2 and TLR4 (A). To test the responsiveness of arterial DCs to triggering with blood-born TNF-α or TLR ligands, we implanted pieces of arteries into SCID mice. 7–10 d after implantation, the SCID mouse chimeras were injected with 2 μg i.v. TNF-α, 10 μg i.v. LPS, or 100 μl i.p. CFA, and the arterial grafts were harvested 48 h later. Tissue extracts from the explanted grafts were analyzed for the mRNA transcripts of β-actin, CD83, IL-18, and the chemokines CCL18, CCL19, and CCL21. After stimulation with blood-born triggers, arterial wall DCs expressed CD83+ and began to produce an array of chemokines. The effect of TNF-α was limited to the induction of CCL21, whereas LPS induced the full spectrum of chemokines. One experiment representative of three is shown (B). Immunohistochemistry confirmed that arterial DCs from LPS-treated (left), but not control (right), arteries expressed CD83 (blue) and produced CCL21 (red) (C). Original magnification, 200 (except LPS-treated CD83 and CCL21 images, which were 600×). P, positive PCR control; N, untreated mouse control; and W, negative PCR control.
Mentions: Considering the critical role of DCs in the vasculitic response, we wanted to explore whether DCs indigenous to the adventitia that are physiologically in a resting state could be stimulated to differentiate in vivo. DCs respond to their microenvironment through a number of different receptors, of which TLRs play an important role (25). To determine the TLR profile expressed by adventitial DCs under normal conditions, we amplified by PCR tissue extracts from normal temporal arteries with primers specific for TLR2 and TLR4. TLR2- and TLR4-specific sequences were present in all normal temporal arteries (Fig. 4 A). To examine DC activation in vivo, temporal arteries from patients who had neither GCA nor PMR were engrafted into SCID mice, and the chimeras were injected with a panel of mediators known to activate DCs. The temporal arteries were explanted and analyzed for transcripts typically produced by activated DCs.

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