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FRI0211 The role of NKG2D, CX3CR1 and TLR4 in the pathogenesis of giant cell arteritis
  1. J. Al-Massad1,
  2. C. Dejaco2,
  3. C. Duftner3,
  4. T. Ness4,
  5. H. Haller1,
  6. M. Schirmer5,
  7. A.D. Wagner1
  1. 1Department of Nephrology, Medical School Hannover, Hannover, Germany
  2. 2Department of Rheumatology, University Graz, Graz
  3. 3Department of Internal Medicine, Hospital Kufstein, Kufstein, Austria
  4. 4Department of Ophthamology, University Hospital Freiburg, Freiburg, Germany
  5. 5Department of Rheumatology, Medical University Innsbruck, Innsbruck, Austria

Abstract

Background Pattern recognition receptors like NKG2D [1] and TLR4 [2] together with chemokine receptors like CX3CR1 [3] are important mediators of innate immunity.

Objectives The study was performed to assess the expression of NKG2D, CX3CR1 and TLR4 on T-cells in temporal arteries from patients with giant cell arteritis (GCA) and to compare findings with results from peripheral blood analysis.

Methods Temporal artery biopsies were obtained from 19 patients diagnosed with GCA and from 9 patients without GCA. For analysis of peripheral blood T-cells from consecutive patients with GCA (n=16) and PMR (n=78) were investigated. Immunohistochemical staining was performed on paraffin-embedded temporal arteries using anti-CD3, anti-CD4, anti-CD8 and anti-NKG2D (monoclonal antibodies) as well as anti-CX3CR1 and anti-TLR4 (polyclonal antibodies) according to a routine protocol. For assessment of circulating T-cells anti-CD4, anti-CD8, anti-CD28, anti-NKG2D, anti-CX3CR1 and anti-TLR4 mAbs were used and cells were analyzed by flow cytometry. Statistical analysis was performed using SPSS.

Results Immunohistochemical analysis of temporal arteries confirmed CD4+ T-cells as the dominant T-cell population in GCA showing a ratio of 70/30 compared with CD8+ T-cells. Most pronounced expression of NKG2D was shown in the media and adventitia compared to intima. Immunofluorescence double-staining confirmed the expression of NKG2D on every fifth CD3+ T-cell especially in the adventitia near the vasa vasorum. The expression of NKG2D showed no dependence on a therapy with glucocorticoids over time. The chemokine receptor CX3CR1 and the toll-like receptor TLR4 accumulated in the adventitia of temporal arteries. Likewise CX3CR1+CD3+ and TLR4+CD3+ T-cells were detected on every fifth and third T-cell, respectively. Biopsies of the control group compared to the GCA group showed statistically significant lower numbers of NKG2D-, CX3CR1- and TLR4-positive cells as determined by student’s t-test. In peripheral blood analysis we found NKG2D, CX3CR1 and TLR4 particularly on senescent CD4+CD28- T-cells (NKG2D: 23.1±24.0% out of CD4+CD28-cells, p<0.001 compared to CD4+CD28+ cells; CX3CR1: 62.7±22.8%, p<0.001 TLR4 4.7±11.1%, p<0.001) whereas expression was negligible on CD4+CD28+. In the CD8+ T-cell subset, NKG2D was expressed in >95% of cells with comparable levels between CD8+CD28- and CD8+CD28+ T-cells. CX3CR1 was present in the CD8+CD28- subset only (65.8±20.2%, p<0.001 compared to CD8+CD28+cells) and TLR4 was not expressed on CD8+ T-cells.

Conclusions The expression of NKG2D is indicative of co-stimulative activity. The finding of CX3CR1 on T-cells close to vasa vasorum might be in accordance with leucocyte extravasation. The expression of TLR4 on T-cells most likely with the loss of the co-stimulatory surface glycoprotein CD28 represents a link between the adaptive and the innate immune system and might be indicative for an alternative signaling pathway in the pathophysiology of GCA.

  1. Maasho K et al. J Immunol, 2005; 174: 4480-4484.

  2. Raffeiner B et al. Arthritis Res Ther. 2005; 7:1412-1420.

  3. Umehara H et al. Arterioscler Thromb Vasc Biol. 2004; 24: 34-30.

Disclosure of Interest None Declared

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