Laboratory investigationElevated Soluble Fas in Aqueous Humor of Patients With Behçet's Uveitis: Correlation With Uveitis Severity
Introduction
Multicellular organisms maintain their integrity by complex mechanisms that ensure a balance between cell proliferation, cell differentiation, and cell death. The death of useless or unwanted cells during embryogenesis, tissue remodeling, immune system development, tumor regression, and normal tissue turnover is called programmed cell death. This is because programmed cell death involves the activation of a suicide machinery that is under genetic control.1 Cell death can be elicited by a number of stimuli, such as growth factor deprivation, ionizing radiation, or the triggering of specific cellular receptors, such as the tumor necrosis factor (TNF) receptor 1 or Fas/APO-1.2
The Fas/Apo-1 molecule is a cell surface receptor belonging to the TNF-α family of apoptosis-signaling molecules and is constitutively expressed in various tissues.3, 4 The triggering of Fas by its ligand results in rapid induction of apoptosis in susceptible cells. Fas ligand (FasL) is a 40-kDa type II integral membrane protein and a member of the TNF family. It is expressed constitutively in a few cells such as CD8 (+) T cells, dendritic cells, and NK cells.5, 6, 7 The tissue distribution of Fas and FasL suggests that the Fas/FasL system plays an important role in the homeostasis of the immune system. The Fas/FasL system has also been addressed as a mediator of the immune privilege in a variety of tissues. The expression of FasL by testicular Sertoli cells and by parenchymal cells of the anterior chamber of the eye enables these cells to kill invading activated Fas-expressing T cells, conferring a state of immune privilege to these sites.8, 9
Fas and FasL can occur in both membrane-bound and soluble forms. The soluble Fas (sFas), which is generated by alternative splicing of the primary Fas transcript, competes for FasL and is able to prevent FasL binding to Fas, thereby blocking Fas-mediated apoptosis.10, 11 When Fas-mediated apoptosis is inhibited, autoreactive cells may escape apoptosis and provoke an autoimmune response resulting in tissue destruction. In several autoimmune diseases, it has been suggested that elevated sFas levels may inhibit apoptosis of autoreactive cells, and eventually lead to the progression of many diseases.12, 13, 14, 15 Although the immunopathogenesis of noninfectious uveitis is still controversial, it is believed to have a putative autoimmune component.16 The aim of this study is to determine the levels of sFas in patients with uveitis and then to correlate the levels with uveitis severity.
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Patients
This study was conducted in accordance with the principles embodied in the Declaration of Helsinki, and informed consent was obtained from all patients and healthy controls. Forty patients with uveitis (25 male and 15 female, mean age = 45.8 years, ranging from 13–68 years) being treated at the Kangnam St. Mary's Hospital between January 1998 and February 1999 were enrolled in this study. The patients with uveitis comprised 24 with Behçet's disease, 6 pan-uveitis, 5 anterior uveitis, 2
Levels of sFas in Serum and Aqueous Humor
Figure 1 shows that the sFas concentration in the AH of uveitis patients (n = 40) was significantly higher than that in the non-uveitis controls (n = 27) (416 ± 54 versus 219 ± 25 pg/mL, P < .001). However, the serum concentration of sFas was not significantly different between the uveitis patients and non-uveitis controls (301 ± 17 versus 308 ± 21 pg/mL, respectively). In the paired samples of serum and AH, obtained simultaneously, the aqueous sFas in patients with uveitis was significantly
Discussion
The eye is a representative organ of an immune-privileged site. One of the mechanisms contributing to this immune privilege may be Fas-FasL-mediated apoptosis occurring within the eye.9 FasL is constitutively expressed in murine ocular tissue such as the iris ciliary body and corneal epithelium. Therefore, inflammatory cells entering the anterior chamber undergo apoptosis and thus produce no tissue damage. In contrast, immune tolerance was not observed in the animal model with a defect in
Acknowledgements
This study was supported by a grant from the Catholic Research Institute of Medical Science, Seoul, Korea. The authors are grateful to Dr. Jeong-Ah Shin for her assistance.
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