Frequencies of IL-15Rα+ cells in patients with Behçet’s disease and the effects of overexpressing IL-15Rα+ on disease symptoms in mice
Introduction
Behcet's disease (BD) is a chronic multi-systemic inflammatory disease presented by oral ulcer, genital ulcer, skin ulcer, and ocular inflammation. BD frequently involves joints, intestine, and the central nervous system [1]. Its pathogenic mechanism remains elusive. However, viral, genetic, and immunological factors are likely to be involved [2]. Viral hypothesis is based on the detection of viruses in saliva and oral tissues from BD patients with ulcer [3], [4]. ICR mice inoculated with herpes simplex virus (HSV) has been developed as an animal model showing BD-like symptoms such as oral ulcers, genital ulcer, skin ulcers, eye symptoms, intestinal ulcers, arthritis, neural involvement, and skin crust [5]. It has been suggested that HSV might play an important role in the pathogenesis in BD patients [6] and BD model mice [5]. HSV-1 DNA and higher serum antibodies against HSV have been reported in BD patients than those in normal controls [7], [8].
Interleikin-15 (IL-15) is a pleiotropic proinflammatory cytokine produced by activated dendritic cells, macrophages, and monocytes [9], [10], [11] essential for cell survival, cell proliferation, and functional activity of immune cells such as natural killer (NK) cells, memory T cells, monocytes, macrophages, and dendritic cells. IL-15 stimulates B cells to proliferate and secrete immunoglobulins [12], [13]. IL-15 is also involved in the pathogenesis of diverse inflammatory diseases including BD [14]. IL-15 exerts its effect by binding to a membrane receptor composed of high affinity binding alpha chain (IL-15Rα) [15] that forms a heterotrimeric receptor complex with IL-15Rβ and IL-15Rγ [16]. IL-15Rα is expressed independently of IL-15Rβγ in humans and mice [17]. IL-15Rα restricts aberrant immune stimulation and decreases the risk of uncontrolled IL-15 exposure [18]. IL-15Rα chain serves as a protector in the cell membrane. The importance of IL-15 for the production and survival of memory CD8 T cells has been shown using virus infected IL-15 knockout mice [19], [20]. It has been reported that the combination of human IL-15 and mouse IL-15Rα-Fc results in significant proliferation of NK cells and NKT cells in mouse in vivo [21].
Higher expressions of IL-15 have been observed in serum, cerebrospinal fluid, and aqueous humor of BD patients [22], [23], [24]. However, whether overexpressing IL-15Rα could be used as a treatment for BD is currently unclear. Therefore, the purpose of this study was to determine whether overexpressing IL-15Rα could affect BD symptoms in a mouse model.
Section snippets
Behçet's disease patients
A total of 26 BD patients who presented for the first time or were monitored at the Department of Dermatology, Ajou University Hospital, were enrolled for this study. Clinical characteristics and therapeutic histories of these patients are shown in Tables 1 and 2, respectively. All patients were diagnosed as BD according to International Study Group Criteria for BD [25]. BD activity index was calculated as outlined in the BD Current Activity Form 2006
Frequencies of IL-15Rα+ cells were down-regulated in PBL of BD patients
Frequencies of IL-15Rα+ PBL in active BD patients (n = 15), inactive BD patients (n = 11), and healthy controls (n = 11) were determined by FACS analysis. In granulocytes, frequencies of IL-15Rα+ cells from active BD patients were significantly down-regulated than those from healthy controls (4.45 ± 2.89% vs. 7.78 ± 5.62%, p = .01) (Fig. 1A). Proportions of NK cells representing CD56+ cells were also significantly lower in active BD patients compared to those in healthy controls (38.90 ± 17.89%
Discussion
Prominent IL-15 expressions are known to be associated with abnormal inflammatory conditions [33]. It has been shown that several inflammatory diseases such as rheumatoid arthritis (RA) [34], [35], systemic lupus erythematosus (SLE) [36], inflammatory bowel disease (IBD) [37], polymyositis [38], and other systemic rheumatic diseases [22] have high levels of IL-15 in peripheral blood compared to healthy controls. IL-15 levels are also higher in mucosal specimens of ulcerative colitis (UC) than
Acknowledgments
This work was supported by a grant (2017R1D1A1B03032168) of Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea. This research was also supported by a grant (HI15C2483) of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea. pIL-15Rα and pIL-15/IL-15Rα were kindly provided
Authors contributions
S.S., and E.S.L. conceived and lead the project. S.S. designed and supervised the animal experiments. E.S.L supervised the human study. S.M.S.I., B.C., and J.C. performed all the experiments and data collection. S.S., and S.M.S.I. wrote the manuscript. All of the authors read and approved the final manuscript.
Conflicts of Interest
The authors have no conflicts of interest to disclose.
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