Objective. Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4؉ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR).Methods. A prospective study of the phenotype and the function of major CD4؉ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. Results. Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased.Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161؉CD4؉ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1.Conclusion. This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161؉CD4؉ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR.Giant cell arteritis (GCA) is a systemic vasculitis affecting large and medium-sized blood vessels. GCA is characterized by granulomatous infiltration into the layers of the aorta and its major branches in association with systemic inflammation, leading to anemia, polymyalgias, and weakness. Classic clinical features of GCA include temporal headache, scalp tenderness, or tender

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Thrombotic manifestations are a hallmark of many auto-immune diseases (AID), specially of warm autoimmune hemolytic anemia (wAIHA), as 15 to 33% of adults with wAIHA experience venous thromboembolic events (VTE). However, beyond the presence of positive antiphospholipid antibodies and splenectomy, risk factors for developing a VTE during wAIHA have not been clearly identified. The aim of this retrospective study was to characterize VTEs during wAIHA and to identify risk factors for VTE. Forty-eight patients with wAIHA were included, among whom 26 (54%) had secondary wAIHA. Eleven (23%) patients presented at least one VTE, that occurred during an active phase of the disease for 10/11 patients (90%). The frequency of VTE was not different between primary and secondary AIHA (23.7 vs. 19.2%; p = 0.5). The Padua prediction score based on traditional risk factors was not different between patients with and without VTE. On multivariate analysis, total bilirubin ≥ 40 μmol/L [odds ratio (OR) = 7.4; p = 0.02] and leucocyte count above 7x109/L (OR = 15.7; p = 0.02) were significantly associated with a higher risk of thrombosis. Antiphospholipid antibodies were screened in 9 out the 11 patients who presented a VTE and were negative. Thus, the frequency of VTE is high (23%) during wAIHA and VTE preferentially occur within the first weeks of diagnosis. As no clinically relevant predictive factors of VTE could be identified, the systematic use of a prophylactic anticoagulation should be recommended in case of active hemolysis and its maintenance after hospital discharge should be considered. The benefit of a systematic screening for VTE and its procedure remain to be determined.

Key Words: LXR Ⅲ RAR Ⅲ macrophages Ⅲ phagocytosis Ⅲ transglutaminase L iver X receptors (LXRs) ␣ and ␤ are nuclear receptors activated by oxysterols. 1,2 They control the expression of genes involved in lipid metabolism and inflammation. 3 LXR␣ is expressed primarily in liver, intestine, adipose tissue, and macrophages, whereas LXR␤ is widely expressed. 1,2 Because LXRs, especially LXR␣, are present at high levels in macrophages, the effects of LXR activation or repression on macrophage functions have been widely investigated. 3,4 Strong evidence suggests that LXRs are master regulators of cholesterol metabolism in these cells. LXR activation improves cholesterol homeostasis and stimulates cholesterol efflux through the coordinated regulation of apolipoprotein E and cholesterol transporters such as ABCA1 (ATP-binding cassette subfamily A member 1) and ABCG1 (ATP-binding cassette subfamily G member 1). [5][6][7] LXRs agonists also modulate the functions of macrophages in innate immunity and inflammation. Synthetic LXR agonists attenuate the inflammatory response of murine macrophages exposed to lipopolysaccharides 8 and increase macrophage survival in response to bacterial infection. 9 In humans, short-term exposure of macrophages to LXR agonists also reduces the inflammatory effects of lipopolysaccharides whereas longterm exposure increases macrophage response to lipopolysaccharides through Toll-like receptor 4 upregulation. 10 Macrophages come from the differentiation of peripheral blood monocytes, which are produced in the bone marrow by differentiation of stem cells, circulate in the blood Ϸ1 to 3 days, and then are recruited in tissues where they undergo differentiation. The role of LXRs has been less studied in monocytes than in macrophages but synthetic LXR agonists MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Human peripheral blood monocytes were obtained from healthy donors, purified with the Monocyte Isolation Kit II (Miltenyi Biotec), and differentiated into macrophages with macrophagecolony stimulating factor. Mouse bone marrow-derived macrophages were collected from wild-type (WT) or LXR␣/␤ knockout (KO) mouse tibias and femurs. Microarray procedures were performed by Miltenyi Biotec; quantitative polymerase chain reaction (PCR) was performed by using a SYBR Green Real-time PCR kit (Invitrogen) on a LightCycler 2.0 detection system (Roche Diagnostics); chromatin immunoprecipitation was performed by using a ChIP-IT kit (Active Motif); and luciferase reporter assays were performed with the Dual Glo Luciferase Assay System (Promega). All-trans retinoic acid levels in human atherosclerotic plaques were determined by liquid chromatography-mass spectrometry (LC-MS). Phagocytosis was measured in macrophages incubated with 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester-stained apoptotic NB4 cells and analyzed with a LSRII flow cytometer (Becton Dickinson). Data are meansϮSD and Mann-Whitney U test was used to determine their sig...