Limits...
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.

Show MeSH

Related in: MedlinePlus

Tissue production of CCL19 and CCL21 in temporal arteries from patients with GCA or PMR and in normal arteries. Temporal arteries were collected, and cDNA was generated. Transcripts for β-actin, CCL19 (top), and CCL21 (bottom) were determined by quantitative PCR. cDNA concentrations were adjusted to 2 × 105 β-actin copies. The number of chemokine transcripts is presented as box plots, with the median and 25th and 75th percentiles as the box, and the whiskers signify the 10th and 90th percentiles. Normal arteries contained minimal copies of CCL19 and CCL21 mRNA. Abundant transcripts for both chemokines were present in arteries with GCA. Arteries from patients with PMR, despite the lack of inflammatory infiltrates, contained intermediate numbers of CCL19 and CCL21 mRNA transcripts.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211768&req=5

fig2: Tissue production of CCL19 and CCL21 in temporal arteries from patients with GCA or PMR and in normal arteries. Temporal arteries were collected, and cDNA was generated. Transcripts for β-actin, CCL19 (top), and CCL21 (bottom) were determined by quantitative PCR. cDNA concentrations were adjusted to 2 × 105 β-actin copies. The number of chemokine transcripts is presented as box plots, with the median and 25th and 75th percentiles as the box, and the whiskers signify the 10th and 90th percentiles. Normal arteries contained minimal copies of CCL19 and CCL21 mRNA. Abundant transcripts for both chemokines were present in arteries with GCA. Arteries from patients with PMR, despite the lack of inflammatory infiltrates, contained intermediate numbers of CCL19 and CCL21 mRNA transcripts.

Mentions: The functional capabilities of DCs change fundamentally as the cells make the transition from the resting to the activated state. To examine the functional profile of vascular DCs in situ, we semi-quantified the production of chemokine transcripts in tissue extracts collected from 12 normal arteries, 18 arteries from patients with PMR, and 16 arteries from patients with GCA. As shown in Fig. 2 , normal arteries were negative for CCL19-specific transcripts and expressed a low level of CCL21-specific sequences (median of 202 copies). In noninflamed arteries, there were no cells that stained with CCL19- or CCL21-specific Ab (unpublished data). In contrast, transcripts for both CCL19 and CCL21 were readily detected in arteries from patients with PMR, supporting the finding that DCs in these tissues are no longer resting. Concentrations of CCL19 and CCL21 mRNA copies in the arteries from the PMR patients did not reach the levels found in full-blown vasculitis. In the samples with fully developed GCA, copies for CCL19 were increased eightfold above controls (median of 1,543 copies), and copies for CCL21 were 24-fold higher (median of 7,662 copies) than in normal arteries. In immunohistochemical studies, the major source of CCL19 and CCL21 protein was CD83+ DCs (unpublished data).


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)

Tissue production of CCL19 and CCL21 in temporal arteries from patients with GCA or PMR and in normal arteries. Temporal arteries were collected, and cDNA was generated. Transcripts for β-actin, CCL19 (top), and CCL21 (bottom) were determined by quantitative PCR. cDNA concentrations were adjusted to 2 × 105 β-actin copies. The number of chemokine transcripts is presented as box plots, with the median and 25th and 75th percentiles as the box, and the whiskers signify the 10th and 90th percentiles. Normal arteries contained minimal copies of CCL19 and CCL21 mRNA. Abundant transcripts for both chemokines were present in arteries with GCA. Arteries from patients with PMR, despite the lack of inflammatory infiltrates, contained intermediate numbers of CCL19 and CCL21 mRNA transcripts.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Tissue production of CCL19 and CCL21 in temporal arteries from patients with GCA or PMR and in normal arteries. Temporal arteries were collected, and cDNA was generated. Transcripts for β-actin, CCL19 (top), and CCL21 (bottom) were determined by quantitative PCR. cDNA concentrations were adjusted to 2 × 105 β-actin copies. The number of chemokine transcripts is presented as box plots, with the median and 25th and 75th percentiles as the box, and the whiskers signify the 10th and 90th percentiles. Normal arteries contained minimal copies of CCL19 and CCL21 mRNA. Abundant transcripts for both chemokines were present in arteries with GCA. Arteries from patients with PMR, despite the lack of inflammatory infiltrates, contained intermediate numbers of CCL19 and CCL21 mRNA transcripts.
Mentions: The functional capabilities of DCs change fundamentally as the cells make the transition from the resting to the activated state. To examine the functional profile of vascular DCs in situ, we semi-quantified the production of chemokine transcripts in tissue extracts collected from 12 normal arteries, 18 arteries from patients with PMR, and 16 arteries from patients with GCA. As shown in Fig. 2 , normal arteries were negative for CCL19-specific transcripts and expressed a low level of CCL21-specific sequences (median of 202 copies). In noninflamed arteries, there were no cells that stained with CCL19- or CCL21-specific Ab (unpublished data). In contrast, transcripts for both CCL19 and CCL21 were readily detected in arteries from patients with PMR, supporting the finding that DCs in these tissues are no longer resting. Concentrations of CCL19 and CCL21 mRNA copies in the arteries from the PMR patients did not reach the levels found in full-blown vasculitis. In the samples with fully developed GCA, copies for CCL19 were increased eightfold above controls (median of 1,543 copies), and copies for CCL21 were 24-fold higher (median of 7,662 copies) than in normal arteries. In immunohistochemical studies, the major source of CCL19 and CCL21 protein was CD83+ DCs (unpublished data).

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