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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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Activated arterial DCs are capable of stimulating T cells. Temporal artery–SCID mouse chimeras were generated by implanting normal temporal arteries from HLA-DRB1*0401+ donors. 6 d after implantation, the chimeras received 10 μg LPS or PBS i.v., and 30 h later, 5 × 106 alloreactive human T cell clones specific for HLA-DRB1*0401 or T cell lines derived from arterial tissue of patients with GCA were adoptively transferred into the mice. Arterial grafts were explanted and embedded in OCT. To locate human T cells in the arterial grafts, frozen tissue sections were immunostained with anti-CD3 Ab. One experiment representative of five is shown. CD3+ T cells (brown) were found in the arteries explanted from the chimeras that had been treated with LPS and had received the T cells. Tissue-infiltrating T cells accumulated along the adventitia–media junction (A and B). In the absence of LPS pretreatment, human T cells were rarely detected in the arteries (D). Grafts from animals that had received neither LPS nor T cells were free of human T cells (C). Original magnification, 200 (A, C, and D) and 400 (B).
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fig5: Activated arterial DCs are capable of stimulating T cells. Temporal artery–SCID mouse chimeras were generated by implanting normal temporal arteries from HLA-DRB1*0401+ donors. 6 d after implantation, the chimeras received 10 μg LPS or PBS i.v., and 30 h later, 5 × 106 alloreactive human T cell clones specific for HLA-DRB1*0401 or T cell lines derived from arterial tissue of patients with GCA were adoptively transferred into the mice. Arterial grafts were explanted and embedded in OCT. To locate human T cells in the arterial grafts, frozen tissue sections were immunostained with anti-CD3 Ab. One experiment representative of five is shown. CD3+ T cells (brown) were found in the arteries explanted from the chimeras that had been treated with LPS and had received the T cells. Tissue-infiltrating T cells accumulated along the adventitia–media junction (A and B). In the absence of LPS pretreatment, human T cells were rarely detected in the arteries (D). Grafts from animals that had received neither LPS nor T cells were free of human T cells (C). Original magnification, 200 (A, C, and D) and 400 (B).

Mentions: To investigate whether triggering of adventitial DCs was sufficient to establish T cell responses in the arterial wall, normal temporal arteries were selected from HLA-DRB1*0401+ donors. The arteries were implanted into SCID mice, and 6 d later, the mice were injected with LPS. 30 h after the LPS injection, 5 × 106 HLA-DRB1*0401–specific alloreactive human T cell clones were adoptively transferred into the chimeras. The arteries, which were explanted 18 d after implantation, were enlarged and surrounded by highly inflamed perivascular tissue. Immunohistochemistry demonstrated the accumulation of tissue-infiltrating human T cells in the graft (Fig. 5, A and B) . Human CD3+ T cells accumulated in the proximal adventitia and in the distal media, the site of DC localization. In contrast, adoptive transfer of alloreactive human T cell clones without prior LPS administration was not sufficient to induce the retention of human T cells in the artery wall (Fig. 5 D).


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)

Activated arterial DCs are capable of stimulating T cells. Temporal artery–SCID mouse chimeras were generated by implanting normal temporal arteries from HLA-DRB1*0401+ donors. 6 d after implantation, the chimeras received 10 μg LPS or PBS i.v., and 30 h later, 5 × 106 alloreactive human T cell clones specific for HLA-DRB1*0401 or T cell lines derived from arterial tissue of patients with GCA were adoptively transferred into the mice. Arterial grafts were explanted and embedded in OCT. To locate human T cells in the arterial grafts, frozen tissue sections were immunostained with anti-CD3 Ab. One experiment representative of five is shown. CD3+ T cells (brown) were found in the arteries explanted from the chimeras that had been treated with LPS and had received the T cells. Tissue-infiltrating T cells accumulated along the adventitia–media junction (A and B). In the absence of LPS pretreatment, human T cells were rarely detected in the arteries (D). Grafts from animals that had received neither LPS nor T cells were free of human T cells (C). Original magnification, 200 (A, C, and D) and 400 (B).
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Activated arterial DCs are capable of stimulating T cells. Temporal artery–SCID mouse chimeras were generated by implanting normal temporal arteries from HLA-DRB1*0401+ donors. 6 d after implantation, the chimeras received 10 μg LPS or PBS i.v., and 30 h later, 5 × 106 alloreactive human T cell clones specific for HLA-DRB1*0401 or T cell lines derived from arterial tissue of patients with GCA were adoptively transferred into the mice. Arterial grafts were explanted and embedded in OCT. To locate human T cells in the arterial grafts, frozen tissue sections were immunostained with anti-CD3 Ab. One experiment representative of five is shown. CD3+ T cells (brown) were found in the arteries explanted from the chimeras that had been treated with LPS and had received the T cells. Tissue-infiltrating T cells accumulated along the adventitia–media junction (A and B). In the absence of LPS pretreatment, human T cells were rarely detected in the arteries (D). Grafts from animals that had received neither LPS nor T cells were free of human T cells (C). Original magnification, 200 (A, C, and D) and 400 (B).
Mentions: To investigate whether triggering of adventitial DCs was sufficient to establish T cell responses in the arterial wall, normal temporal arteries were selected from HLA-DRB1*0401+ donors. The arteries were implanted into SCID mice, and 6 d later, the mice were injected with LPS. 30 h after the LPS injection, 5 × 106 HLA-DRB1*0401–specific alloreactive human T cell clones were adoptively transferred into the chimeras. The arteries, which were explanted 18 d after implantation, were enlarged and surrounded by highly inflamed perivascular tissue. Immunohistochemistry demonstrated the accumulation of tissue-infiltrating human T cells in the graft (Fig. 5, A and B) . Human CD3+ T cells accumulated in the proximal adventitia and in the distal media, the site of DC localization. In contrast, adoptive transfer of alloreactive human T cell clones without prior LPS administration was not sufficient to induce the retention of human T cells in the artery wall (Fig. 5 D).

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