MRL/lpr 마우스 모델을 이용한 루푸스 신염에서의 IP-10의 역할 규명 = Role of IP-10 in Lupus nephritis using MRL/lpr Mouse Model

다국어 초록 (Multilingual Abstract)

Background. Lupus nephritis (LN) is a form of renal inflammation that occurs as a complication of systemic lupus erythematosus (SLE), an autoimmune disease. Among the various chemokines implicated in lupus nephritis (LN) pathogenesis, interferon-γ-inducible protein 10 (IP-10) is a major mediator that recruits immune cells and induces inflammation. Secreted IP-10 promotes the migration of CD8⁺ T cells and NK cells to the inflammatory site, inducing an inflammatory response in the kidneys and causing tissue damage. T stem-like cells have been shown to differentiate into terminally exhausted T-cells in chronic infection models when IP-10 levels increase or persist during chronic inflammation. However, it remains unclear whether CD8⁺ T-cells differentiate into the exhausted lineage and if IP-10 influences T-cell exhaustion in LN.
Objective. This study aims to determine the role of IP-10 in the reduction of T stem-like cells and accumulation of terminally exhausted T-cells in LN.
Methods. Proteome profiler screening was performed on plasma samples obtained from patients with SLE (n=6), LN (n=6), and healthy controls (n=6). In MRL/lpr mice, serum was acquired bi-weekly from weeks 10 to 24, and the levels of serum anti-dsDNA, cytokines (BAFF, IL-16, CD30, Leptin, TIM-3, and VEGF), and chemokines (IP-10, MCP-1, MIG, and I-TAC) were measured using ELISA and Luminex assays. To evaluate CD8+ T cell differentiation in tissues, the spleen and kidney tissues was obtained and analyzed by flow cytometry at 10, 14, 18, and 24 weeks of age.
Results. Human Proteome profiler analysis of plasma samples showed that IP-10, MCP-1, I-TAC, and MIG levels were significantly higher in patients with SLE and LN than in healthy controls. Correlation analysis of these factors revealed that in patients with LN, IP-10 was strongly associated with other immunoregulatory factors, such as MCP-1 and TIM-3. In the MRL/lpr mouse model, serum IP-10 levels increased with age and correlated with BAFF and anti-dsDNA levels Additionally, flow cytometry analysis of spleen from MRL/lpr mice revealed that T stem-like cells (TCF1+CX3CR1+CD8+) within the tissue decreased and differentiated into an exhausted state, leading to the accumulation of terminally exhausted T-cells (TCF1-CX3CR1-CD8+) correlating with serum IP-10 levels. In the kidneys of MRL/lpr mice, terminally exhausted T-cells and IP-10 levels increased with age, showing a significant association over time.
Conclusions. The increase in serum IP-10 in MRL/lpr mice may be associated with immunological changes in the spleen and renal tissues, including a decrease in T stem-like cells and accumulation of terminally exhausted T-cells. Therefore, the ratio of T stem-like cells to terminally exhausted T-cells may be an important indicator of immune dysregulation in LN. Further research is expected to elucidate IP-10 as a potential regulator of terminally exhausted T-cells differentiation in LN.

목차 (Table of Contents)

• Abstract i
• Contents iii
• List of Figures iv
• List of Abbreviation v
• Introduction 1
• Materials and Methods 6
• Results 9
• Discussion 30
• Conclusion 35
• References 36
• 국문 요약 43