PP22. GLUCOCORTICOIDS INHIBIT APOPTOSIS OF PERIPHERAL CD1C+ DENDRITIC CELLS AND CAUSE A DOWN-REGULATION OF THE CHEMOKINE LIGANDS CCL19 AND CCL21 IN GRANULOMATOUS INFILTRATES IN TEMPORAL ARTERIES FROM PATIENTS WITH GIANT CELL ARTERITIS

Abstract

Background: Giant cell arteritis (GCA) is a systemic granulomatous vasculitis and characterized by a prompt response to glucocorticoid therapy. Earlier studies demonstrated that dendritic cells (DC) play a major role in the pathogenesis of GCA. Due to apoptosis glucocorticoid therapy leads to a rapid, time-dependent normalization of DC in temporal arteries from GCA patients. The aim of this study was to detemine glucocorticoid regulated genes in DC of GCA patients and whether glucocorticoid influences chemokines like CCL19 and CCL21 which promote DC migration from the blood stream into the granulomatous lesions. Methods: Affymetrix U95Av2 arrays were used to determine glucocorticoid regulated genes in CD1c+ peripheral blood DC from 10 GCA patients. Immunohistochemical staining was performed on 38 paraffin-embedded consecutive temporal artery specimens from 21 patients with GCA to quantify CCL19 and CCL21 positive cells in granulomatous infiltrates. Results: DNA microarray analysis of CD1c+ peripheral blood DC from glucocorticoid treated GCA patients indicated a down-regulation of caspases 1 and 3, the caspase like apoptosis regulatory protein (CLARP), BAX delta, FAS and FADD was seen. Bcl2 and the inhibitor of apoptosis protein (IAP1) were up-regulated. In temporal arteries from GCA patients glucocorticoid rapidly down-regulated CCL 19 and CCL21 in granulomatous infiltrates. After one day of glucocorticoid therapy 13% (n = 12) of all mononucleated cells in the graulomatous infiltrates express CCL19. The number of CCL19+ cells decreases from 8% after two days (n = 7) to 5% (n = 4) after 7 days of glucocorticoid therapy. A significant down-regulation of CCL19 was already found between day 1 and day 3 of glucocorticoid treatment (p = 0.0032). CCL21+ cells decreased in the same manner under glucocorticoid exposure. Conclusions: Glucocorticoids lead to an inhibition of CD1c+ DC apoptosis in the peripheral blood of GCA patients. Additionally, a time-dependent down-regulation of CCL19 and CCL21 in temporal arteries was found and this might account for an inhibition of DC imigration in temporal artery tissue in GCA.