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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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Stimulation of adoptively transferred T cells by activated arterial DCs. Temporal artery–SCID mouse chimeras carrying HLA-DRB1*0401+ normal arteries were treated with LPS and adoptively transferred with alloreactive human T cells as described in Fig. 5. Explanted arterial grafts were shock frozen and used for the generation of cDNA. cDNA concentrations were adjusted to 2 × 105 β-actin transcripts. Tissue concentrations of β-actin, CD83 (A), IL-18 (B), IFN-γ (C), and CD40L (D) mRNA transcripts were determined by quantitative PCR. Pretreatment with LPS induced prompt activation of DCs as indicated by the up-regulation of CD83 and IL-18 mRNA transcripts. IFN-γ–and CD40L-specific mRNA transcripts were clearly induced in arteries that had been pretreated with LPS and that received human alloreactive T cell clones. In the absence of LPS stimulation, adoptively transferred T cells induced a minimal up-regulation of CD83, but they failed to undergo in situ activation.
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fig6: Stimulation of adoptively transferred T cells by activated arterial DCs. Temporal artery–SCID mouse chimeras carrying HLA-DRB1*0401+ normal arteries were treated with LPS and adoptively transferred with alloreactive human T cells as described in Fig. 5. Explanted arterial grafts were shock frozen and used for the generation of cDNA. cDNA concentrations were adjusted to 2 × 105 β-actin transcripts. Tissue concentrations of β-actin, CD83 (A), IL-18 (B), IFN-γ (C), and CD40L (D) mRNA transcripts were determined by quantitative PCR. Pretreatment with LPS induced prompt activation of DCs as indicated by the up-regulation of CD83 and IL-18 mRNA transcripts. IFN-γ–and CD40L-specific mRNA transcripts were clearly induced in arteries that had been pretreated with LPS and that received human alloreactive T cell clones. In the absence of LPS stimulation, adoptively transferred T cells induced a minimal up-regulation of CD83, but they failed to undergo in situ activation.

Mentions: To determine whether the cotreatment with LPS and human T cells had indeed resulted in the activation of tissue-resident DCs and the recruitment and retention of allospecific T cells, markers of T cell and DC activation were quantified in explanted temporal arteries. As shown in Fig. 6 , in the absence of LPS and T cell transfer, no CD83 and minimal levels of IL-18 were found. Adoptive transfer of the T cell clones alone caused a minor induction of CD83. When LPS stimulation preceded T cell transfer, both markers of DC activation, CD83 and IL-18, were up-regulated. Similar results were obtained for IFN-γ and CD40L, markers for T cell activation in the tissue. Production of IFN-γ as well as CD40L required the sequential treatment with LPS followed by the adoptive transfer of T cells. These experiments demonstrated that triggering of adventitial DCs was sufficient to induce T cell recruitment, retention, and stimulation in the arterial wall.


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)

Stimulation of adoptively transferred T cells by activated arterial DCs. Temporal artery–SCID mouse chimeras carrying HLA-DRB1*0401+ normal arteries were treated with LPS and adoptively transferred with alloreactive human T cells as described in Fig. 5. Explanted arterial grafts were shock frozen and used for the generation of cDNA. cDNA concentrations were adjusted to 2 × 105 β-actin transcripts. Tissue concentrations of β-actin, CD83 (A), IL-18 (B), IFN-γ (C), and CD40L (D) mRNA transcripts were determined by quantitative PCR. Pretreatment with LPS induced prompt activation of DCs as indicated by the up-regulation of CD83 and IL-18 mRNA transcripts. IFN-γ–and CD40L-specific mRNA transcripts were clearly induced in arteries that had been pretreated with LPS and that received human alloreactive T cell clones. In the absence of LPS stimulation, adoptively transferred T cells induced a minimal up-regulation of CD83, but they failed to undergo in situ activation.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Stimulation of adoptively transferred T cells by activated arterial DCs. Temporal artery–SCID mouse chimeras carrying HLA-DRB1*0401+ normal arteries were treated with LPS and adoptively transferred with alloreactive human T cells as described in Fig. 5. Explanted arterial grafts were shock frozen and used for the generation of cDNA. cDNA concentrations were adjusted to 2 × 105 β-actin transcripts. Tissue concentrations of β-actin, CD83 (A), IL-18 (B), IFN-γ (C), and CD40L (D) mRNA transcripts were determined by quantitative PCR. Pretreatment with LPS induced prompt activation of DCs as indicated by the up-regulation of CD83 and IL-18 mRNA transcripts. IFN-γ–and CD40L-specific mRNA transcripts were clearly induced in arteries that had been pretreated with LPS and that received human alloreactive T cell clones. In the absence of LPS stimulation, adoptively transferred T cells induced a minimal up-regulation of CD83, but they failed to undergo in situ activation.
Mentions: To determine whether the cotreatment with LPS and human T cells had indeed resulted in the activation of tissue-resident DCs and the recruitment and retention of allospecific T cells, markers of T cell and DC activation were quantified in explanted temporal arteries. As shown in Fig. 6 , in the absence of LPS and T cell transfer, no CD83 and minimal levels of IL-18 were found. Adoptive transfer of the T cell clones alone caused a minor induction of CD83. When LPS stimulation preceded T cell transfer, both markers of DC activation, CD83 and IL-18, were up-regulated. Similar results were obtained for IFN-γ and CD40L, markers for T cell activation in the tissue. Production of IFN-γ as well as CD40L required the sequential treatment with LPS followed by the adoptive transfer of T cells. These experiments demonstrated that triggering of adventitial DCs was sufficient to induce T cell recruitment, retention, and stimulation in the arterial wall.

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