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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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DC activation in PMR arteries is sufficient to activate disease-relevant T cells from GCA arteries. Donors of normal arteries and patients with PMR or GCA were typed for HLA-DR, and HLA-DRB1*0401+ arteries were selected. Arteries from patients with each diagnosis were implanted individually into SCID mice or three arteries (one from each disease category) were implanted into nonadjacent sites of the same mouse. After 7 d, the grafts were harvested, shock frozen, and used for the generation of cDNA. cDNA concentrations were adjusted to equal numbers of β-actin copies. One experiment representative of three is shown. Tissue-infiltrating T cells were detected by PCR analysis for TCR-α sequences (A). T cell activation in the tissues was assessed by quantifying mRNA transcripts for IFN-γ (B) and CD40L (C) by quantitative PCR. GCA arteries contained abundant TCR-α mRNA (lane 1). No T cells were detected in negative arteries (lanes 4 and 5), which remained free of TCR-α sequences even after coimplantation with inflamed arteries (lane 4). PMR arteries had a minimal signal for TCR-α if implanted individually (lane 3), but they accumulated TCR-α copies when combined with inflamed arteries (lane 2). No IFN-γ or CD40L could be detected in negative arteries. PMR arteries remained negative for IFN-γ and CD40L as long as they were isolated from arteries with typical vasculitic lesions. Once GCA and PMR arteries were combined in the same chimera, T cells from the vasculitic infiltrates migrated into the PMR arteries, where they produced IFN-γ and CD40L (B and C). Copy numbers of IFN-γ and CD40L are shown as mean ± SD for one representative experiment. P, positive PCR control; W, negative PCR control.
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fig7: DC activation in PMR arteries is sufficient to activate disease-relevant T cells from GCA arteries. Donors of normal arteries and patients with PMR or GCA were typed for HLA-DR, and HLA-DRB1*0401+ arteries were selected. Arteries from patients with each diagnosis were implanted individually into SCID mice or three arteries (one from each disease category) were implanted into nonadjacent sites of the same mouse. After 7 d, the grafts were harvested, shock frozen, and used for the generation of cDNA. cDNA concentrations were adjusted to equal numbers of β-actin copies. One experiment representative of three is shown. Tissue-infiltrating T cells were detected by PCR analysis for TCR-α sequences (A). T cell activation in the tissues was assessed by quantifying mRNA transcripts for IFN-γ (B) and CD40L (C) by quantitative PCR. GCA arteries contained abundant TCR-α mRNA (lane 1). No T cells were detected in negative arteries (lanes 4 and 5), which remained free of TCR-α sequences even after coimplantation with inflamed arteries (lane 4). PMR arteries had a minimal signal for TCR-α if implanted individually (lane 3), but they accumulated TCR-α copies when combined with inflamed arteries (lane 2). No IFN-γ or CD40L could be detected in negative arteries. PMR arteries remained negative for IFN-γ and CD40L as long as they were isolated from arteries with typical vasculitic lesions. Once GCA and PMR arteries were combined in the same chimera, T cells from the vasculitic infiltrates migrated into the PMR arteries, where they produced IFN-γ and CD40L (B and C). Copy numbers of IFN-γ and CD40L are shown as mean ± SD for one representative experiment. P, positive PCR control; W, negative PCR control.

Mentions: The expression of CD83 on adventitial DCs and the production of chemokines in arteries from patients with PMR suggested that this disease entity is associated with DC activation, yet a detectable infiltrate of T cells and macrophages has not been established. To examine whether DCs in PMR arteries are indeed activated and have the potential to stimulate T cells, we developed an experimental system that allows for the in vivo transfer of T cells from GCA arteries into arteries lacking T cell infiltrates. Temporal arteries from patients who had unrelated diseases, patients who had PMR, and patients with typical granulomatous infiltrates of GCA were HLA-DR genotyped. We selected arteries that were HLA-DRB1*0401+. This allele is associated with both GCA and PMR and is present in 60–70% of the patients and in 20–25% of the controls. Temporal arteries were cut into two pieces, and SCID mice were implanted with a single arterial specimen from a control donor, a patient with PMR, or a patient with GCA, or they were implanted with a combination of arteries from all three patients. After 7 d, the grafts were explanted and examined for T cell activation. Representative results from three such coimplantation experiments are shown in Fig. 7 .


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)

DC activation in PMR arteries is sufficient to activate disease-relevant T cells from GCA arteries. Donors of normal arteries and patients with PMR or GCA were typed for HLA-DR, and HLA-DRB1*0401+ arteries were selected. Arteries from patients with each diagnosis were implanted individually into SCID mice or three arteries (one from each disease category) were implanted into nonadjacent sites of the same mouse. After 7 d, the grafts were harvested, shock frozen, and used for the generation of cDNA. cDNA concentrations were adjusted to equal numbers of β-actin copies. One experiment representative of three is shown. Tissue-infiltrating T cells were detected by PCR analysis for TCR-α sequences (A). T cell activation in the tissues was assessed by quantifying mRNA transcripts for IFN-γ (B) and CD40L (C) by quantitative PCR. GCA arteries contained abundant TCR-α mRNA (lane 1). No T cells were detected in negative arteries (lanes 4 and 5), which remained free of TCR-α sequences even after coimplantation with inflamed arteries (lane 4). PMR arteries had a minimal signal for TCR-α if implanted individually (lane 3), but they accumulated TCR-α copies when combined with inflamed arteries (lane 2). No IFN-γ or CD40L could be detected in negative arteries. PMR arteries remained negative for IFN-γ and CD40L as long as they were isolated from arteries with typical vasculitic lesions. Once GCA and PMR arteries were combined in the same chimera, T cells from the vasculitic infiltrates migrated into the PMR arteries, where they produced IFN-γ and CD40L (B and C). Copy numbers of IFN-γ and CD40L are shown as mean ± SD for one representative experiment. P, positive PCR control; W, negative PCR control.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211768&req=5

fig7: DC activation in PMR arteries is sufficient to activate disease-relevant T cells from GCA arteries. Donors of normal arteries and patients with PMR or GCA were typed for HLA-DR, and HLA-DRB1*0401+ arteries were selected. Arteries from patients with each diagnosis were implanted individually into SCID mice or three arteries (one from each disease category) were implanted into nonadjacent sites of the same mouse. After 7 d, the grafts were harvested, shock frozen, and used for the generation of cDNA. cDNA concentrations were adjusted to equal numbers of β-actin copies. One experiment representative of three is shown. Tissue-infiltrating T cells were detected by PCR analysis for TCR-α sequences (A). T cell activation in the tissues was assessed by quantifying mRNA transcripts for IFN-γ (B) and CD40L (C) by quantitative PCR. GCA arteries contained abundant TCR-α mRNA (lane 1). No T cells were detected in negative arteries (lanes 4 and 5), which remained free of TCR-α sequences even after coimplantation with inflamed arteries (lane 4). PMR arteries had a minimal signal for TCR-α if implanted individually (lane 3), but they accumulated TCR-α copies when combined with inflamed arteries (lane 2). No IFN-γ or CD40L could be detected in negative arteries. PMR arteries remained negative for IFN-γ and CD40L as long as they were isolated from arteries with typical vasculitic lesions. Once GCA and PMR arteries were combined in the same chimera, T cells from the vasculitic infiltrates migrated into the PMR arteries, where they produced IFN-γ and CD40L (B and C). Copy numbers of IFN-γ and CD40L are shown as mean ± SD for one representative experiment. P, positive PCR control; W, negative PCR control.
Mentions: The expression of CD83 on adventitial DCs and the production of chemokines in arteries from patients with PMR suggested that this disease entity is associated with DC activation, yet a detectable infiltrate of T cells and macrophages has not been established. To examine whether DCs in PMR arteries are indeed activated and have the potential to stimulate T cells, we developed an experimental system that allows for the in vivo transfer of T cells from GCA arteries into arteries lacking T cell infiltrates. Temporal arteries from patients who had unrelated diseases, patients who had PMR, and patients with typical granulomatous infiltrates of GCA were HLA-DR genotyped. We selected arteries that were HLA-DRB1*0401+. This allele is associated with both GCA and PMR and is present in 60–70% of the patients and in 20–25% of the controls. Temporal arteries were cut into two pieces, and SCID mice were implanted with a single arterial specimen from a control donor, a patient with PMR, or a patient with GCA, or they were implanted with a combination of arteries from all three patients. After 7 d, the grafts were explanted and examined for T cell activation. Representative results from three such coimplantation experiments are shown in Fig. 7 .

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