ab21205

Dendritic cells co-localize with activated CD4+ T cells in giant cell arteritis

A.D. Wagner¹, U. Wittkop¹, A. Prahst¹, W.A. Schmidt², E. Gromnica-Ihle², K. Vorpahl³, A.P. Hudson⁴, H. Zeidler¹

¹Medical School Hannover, Hannover; ²Medical Center for Rheumatology, Berlin; ³Institute for Pathology, Helios Klinikum Berlin, Klinikum Buch, Berlin, Germany; ⁴Wayne State University School of Medicine, Detroit, Michigan, USA.

ABSTRACT
Objective
Giant cell arteritis (GCA) is a vasculitis predominantly affecting medium- and large-sized arteries. Recent data show the co-localization of dendritic cells and Chlamydia pneumoniae in vascular biopsies from GCA patients. Here we define the topographical relation of dendritic cells and these activated T-cells to determine the antigen presenting cell in GCA, and to examine several auxiliary biochemical and genetic aspects relating to the role of bacteria such as C. pneumoniae in eliciting GCA.

Methods
18 paraffin-embedded temporal artery biopsy specimens from 14 patients with GCA that were PCR-positive for C. pneumoniae were examined by two-color immunohistochemistry for the topographical relationship between dendritic cells and activated T-cells. In addition the presence of GTP-binding proteins, Tumor necrosis factor alpha (TNFa), and Toll-like receptor 4 (TLR4) was investigated. 15 temporal artery specimens from 10 patients without GCA served as controls.

Results
In all GCA specimens, dendritic cells co-localized in the immediate vicinity of activated CD4+ Talin-expressing T cells, and these were predominantly found in granulomatous infiltrates. Confocal microscopy confirmed the cell-cell contact of dendritic cells with activated T cells. Results further showed that RhoA and Rac1 were predominantly present in the region of granulomatous infiltrates. TNFa production and expression was found in dendritic cells and macrophages, predominantly in granulomatous infiltrates and in endothelial cells of the vasa vasorum dispersed in the adventitial and medial layers of the temporal artery. No control specimens showed TNFa expression. More than 95% of dendritic cells were positive for TLR4; macrophages and endothelial cells localized in the adventitia showed TLR4 production.

Conclusions
The immediate co-localization of dendritic cells and activated T cells indicate a high probability that the former represent the antigen presenting cells in GCA. In addition, because of the presence of Rho A and Rac1 in the granulomatous infiltrates, we speculate that they provide the right environment for cell-cell contact and adhesion, and that they may promote the internalization of bacteria. TNFa is expressed at high levels in the granulomatous infiltrates of temporal artery specimens from patients with GCA. Since TLR4 is produced in the same cell types, and predominantly in the adventitial layer of the temporal artery, we suggest that these receptors are coupled to signal transduction pathways that control TNFa expression.

Key words
Giant cell arteritis, dendritic cells, Chlamydia pneumoniae, antigen presentation.

This work was supported by grants from the Norddeutsche Landesbank Hannover and the Dr. Liesel-Keinath-Stiftung, as well as NIH grant AI-44055.
Please address correspondence to: Dr. Annette Wagner, Division Rheumatology, Hannover Medical School, Carl-Neuberg- Strasse 1, 30625 Hannover, Germany.