(The) role of T cell immunoglobulin mucin domain in herpes simplex virus-induced Behçet’s disease mouse model = 단순포진 바이러스로 유도한 베체트병 마우스 모델에서 T cell immunoglobulin mucin domain (Tim) 의 역할

다국어 초록 (Multilingual Abstract)

The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Individual TIM family members may serve as susceptibility markers for asthma, allergies and autoimmune diseases, as well as potential cell surface markers for T helper type (Th)1 and Th2 T cells. TIM-1 plays an important role in the regulation of immune responses and the development of autoimmune diseases. TIM-4 is a natural ligand of TIM-1, and interaction of TIM-1 and TIM-4 is involved in the regulation of Th cell responses and the modulation of the Th1/Th2 cytokines balance. TIM-4 expression was increased in patients with systemic lupus erythematosus (SLE). It has been also reported that TIM-3 expression was higher in patients with rheumatoid arthritis compared to controls. Further, Galectin-9 (Gal-9) has been identified as a TIM-3 ligand (L) and the TIM-3-TIM-3L interaction serves as a specific down-regulator of the Th1 immune response.
Behçet’s disease (BD) is a chronic, multisystemic inflammatory disorder with arthritic, gastrointestinal, mucocutaneous, ocular, vascular, and central nervous system involvement. In herpes simplex virus induced BD mouse model, the expression of Tim-1 and Gal-9 was lower levels compared to asymptomatic BD normal (BDN) mice. The expression of Tim-3 and Tim-4 was higher in BD mice than BDN mice. In addition, Tim-1 vector injected BD mice showed changes of BD-like symptoms and decreased the severity score. Again, treatment with Tim-4 siRNA also improved the BD-like symptoms and decreased the severity score accompanied with up-regulation of regulatory T cells (Treg). Furthermore, administration of Gal-9 improved the BD-like symptoms, decreased the severity score, and increased Treg cells. In addition, Gal-9 induced improvement was associated with down-regulation of pro-inflammatory cytokines and induction of apoptosis.
In the present study, we showed that the regulation of Tim-1 or Tim-4 affected the BD-like symptoms and Tim-3-Tim-3L interaction improved the inflammatory symptoms in BD mice.

목차 (Table of Contents)

• TABLE OF CONTENTS
• ABSTRACT ⅰ
• TABLE OF CONTENTS ⅲ
• LIST OF FIGURES ⅴ
• LIST OF TABLES ⅶ
• Ⅰ. INTRODUCTION 1
• Ⅱ. MATERIALS AND METHODS 4
• A. Antibodies and reagents 4
• B. Animal experiments 4
• C. BD-like symptoms 5
• D. Tim-1 DNA constructs 5
• E. Preparation of Tim-4 small interfering RNA (siRNA) 6
• F. Tim-1 vector and Tim-4 siRNA administration to BD mice 6
• G. Gal-9 administration to BD mice 6
• H. Flow cytometry 6
• I. Enzyme-linked immunosorbent assay (ELISA) 7
• J. Transmission electron microscopy (TEM) 7
• K. Statistical analysis 8
• Ⅲ. RESULTS 9
• A. The frequencies of Tim-1 and Tim-4 expressing cells in normal healthy, BDN and BD mice 9
• B. The expression of Tim-3 and Gal-9 in BD mice 14
• C. Administration of Tim-1 vector up-regulates the frequency of Tim-1(+) cells in vivo lymph nodes 16
• D. Administration of Tim-1 vector affected the BD-like symptoms 18
• E. Tim-1 vector administration affected the regulatory cellular phenotypes 24
• F. Pro-inflammatory cytokines were down-regulated by Tim-1 vector administration in BD mice 26
• G. Tim-4 siRNA treatment down-regulated the expression of Tim-4 in normal healthy mice 28
• H. Administration of siTim-4 changed BD-like symptoms 30
• I. Treg cells were up-regulated in siTim-4 treated BD mice 35
• J. Treatment with siTim-4 decreased the serum level of IL-17 in BD mice 37
• K. Gal-9 treatment up-regulated the expression of Gal-9 in vitro and in vivo 39
• L. Gal-9 administration improved BD-like symptoms 41
• M. Gal-9 induced the expression of cell death-related molecules in BD mice 43
• N. Gal-9 modulated the cell population in BD mice 47
• O. Gal-9 regulated cytokine expression in BD mice 49
• Ⅳ. DISCUSSION 51
• Ⅴ. CONCLUSION 57
• REFERENCES 58
• 국문요약 70