Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Schroeder Arthritis Institute, Krembil Research Institute, and Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, and Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
Arthritis Rheumatol. 2023 Sep;75(9):1542-1555. doi: 10.1002/art.42482. Epub 2023 Jun 30.
Elevated levels of serum interferon-α (IFNα) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNα levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNα on B cells.
Two classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNα to mimic the sustained elevations of IFNα seen in SLE. The role of B cell IFNα signaling, T cells, and Myd88 signaling was determined using B cell-specific IFNα receptor-knockout, CD4+ T cell-depleted, or Myd88-knockout mice, respectively. Flow cytometry, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNα on the immunologic phenotype.
Elevation of serum IFNα disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNα receptor. Many of the IFNα-mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNα acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells.
The results provide evidence that elevated IFNα levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE.
血清干扰素-α（IFNα）水平升高和 B 细胞耐受破坏是系统性红斑狼疮（SLE）发病机制的核心；然而，这两个过程之间的关系尚不清楚。本研究旨在研究升高的 IFNα 水平对体内 B 细胞耐受机制的影响，并确定观察到的任何变化是否是由于 IFNα 对 B 细胞的直接作用。
使用两种经典的 B 细胞耐受小鼠模型，结合编码 IFNα 的腺病毒载体，模拟 SLE 中持续升高的 IFNα。使用 B 细胞特异性 IFNα 受体敲除鼠、CD4+T 细胞耗竭鼠或 Myd88 敲除鼠，分别确定 B 细胞 IFNα 信号、T 细胞和 Myd88 信号的作用。流式细胞术、酶联免疫吸附试验、实时定量聚合酶链反应和细胞培养用于研究升高的 IFNα 对免疫表型的影响。
血清 IFNα 水平升高破坏了多种 B 细胞耐受机制，并导致自身抗体产生。这种破坏依赖于 B 细胞表达 IFNα 受体。IFNα 介导的许多改变也需要 CD4+T 细胞和 Myd88 的存在，表明 IFNα 直接作用于 B 细胞，改变它们对 Myd88 信号的反应以及与 T 细胞相互作用的能力。
结果提供了证据表明，升高的 IFNα 水平直接作用于 B 细胞，促进自身抗体产生，并进一步强调了 IFN 信号作为 SLE 潜在治疗靶点的重要性。
