Centre for Kidney Research, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.
Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
J Am Soc Nephrol. 2022 May;33(5):966-984. doi: 10.1681/ASN.2021081145. Epub 2022 Apr 6.
The cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy.
We administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice.
BAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19 B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33-treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33-stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)-depleted splenocytes. Wild-type mice infused with IL-33-treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution.
IL-33-expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.
细胞因子 IL-33 是先天淋巴样细胞 2 (ILC2s) 在先天免疫和过敏炎症中的激活剂。B 细胞激活因子 (BAFF) 在 B 细胞增殖和分化中起核心作用，该蛋白的高水平会导致过量的抗体产生，包括 IgA。BAFF 转基因小鼠过表达 BAFF 并自发发展为类似于人类 IgA 肾病的肾小球肾炎。
我们给野生型和 BAFF 转基因小鼠施用 IL-33 或 PBS。在用 IL-33 处理 Rag1 缺陷小鼠后，用或不用抗 CD90.2 来优先耗尽 ILC2s，然后我们分离脾细胞，将其过继转移到 BAFF 转基因小鼠中。
用 IL-33 处理的 BAFF 转基因小鼠出现更严重的肾功能障碍和蛋白尿、肾小球硬化、肾小管间质损伤和 IgA 和 C3 的肾小球沉积。与野生型小鼠相比，BAFF 转基因小鼠脾和肾中的 CD19 B 细胞以及肾和肠中的 ILC2s 增加，用 IL-33 处理后进一步增加。用 IL-33 处理野生型小鼠对肾功能或组织学没有影响，也没有改变脾、肾或肠中 ILC2s 的数量。为了了解 ILC2s 的作用，将来自 IL-33 处理的 Rag1 缺陷小鼠的脾细胞转移到 BAFF 转基因小鼠中。用 IL-33 刺激的 Rag1 缺陷脾细胞转移加重了肾小球肾炎和 IgA 沉积，但用 ILC2（抗 CD90.2）耗竭的脾细胞转移则没有。用 IL-33 处理的 Rag1 缺陷脾细胞输注的野生型小鼠的肾功能、ILC2 数量或分布均无变化。
IL-33 扩增的 ILC2s 在小鼠模型中加重了 IgA 肾小球肾炎。这些发现表明，IL-33 和 ILC2s 值得作为人类 IgA 肾病的可能介导物进行评估。
