Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
Cardiovasc Res. 2021 Mar 21;117(4):1217-1228. doi: 10.1093/cvr/cvaa187.
Elevated serum immunoglobulins have been associated with experimental and human hypertension for decades but whether immunoglobulins and B cells play a causal role in hypertension pathology is unclear. In this study, we sought to determine the role of B cells and high-affinity class-switched immunoglobulins on hypertension and hypertensive end-organ damage to determine if they might represent viable therapeutic targets for this disease.
We purified serum immunoglobulin G (IgG) from mice exposed to vehicle or angiotensin (Ang) II to induce hypertension and adoptively transferred these to wild type (WT) recipient mice receiving a subpressor dose of Ang II. We found that transfer of IgG from hypertensive animals does not affect blood pressure, endothelial function, renal inflammation, albuminuria, or T cell-derived cytokine production compared with transfer of IgG from vehicle infused animals. As an alternative approach to investigate the role of high-affinity, class-switched immunoglobulins, we studied mice with genetic deletion of activation-induced deaminase (Aicda-/-). These mice have elevated levels of IgM but virtual absence of class-switched immunoglobulins such as IgG subclasses and IgA. Neither male nor female Aicda-/- mice were protected from Ang II-induced hypertension and renal/vascular damage. To determine if IgM or non-immunoglobulin-dependent innate functions of B cells play a role in hypertension, we studied mice with severe global B-cell deficiency due to deletion of the membrane exon of the IgM heavy chain (µMT-/-). µMT-/- mice were also not protected from hypertension or end-organ damage induced by Ang II infusion or deoxycorticosterone acetate-salt treatment.
These results suggest that B cells and serum immunoglobulins do not play a causal role in hypertension pathology.
几十年来，血清免疫球蛋白升高与实验性和人类高血压有关，但免疫球蛋白和 B 细胞是否在高血压病理中起因果作用尚不清楚。在这项研究中，我们试图确定 B 细胞和高亲和力类别转换免疫球蛋白在高血压和高血压靶器官损伤中的作用，以确定它们是否可能成为该疾病的可行治疗靶点。
我们从暴露于载体或血管紧张素 (Ang) II 以诱导高血压的小鼠中纯化血清免疫球蛋白 G (IgG)，并将其过继转移至接受亚抑制剂量 Ang II 的野生型 (WT) 受体小鼠。我们发现，与从输注载体的动物中转移的 IgG 相比，从高血压动物中转移的 IgG 不会影响血压、内皮功能、肾脏炎症、蛋白尿或 T 细胞衍生细胞因子的产生。作为研究高亲和力、类别转换免疫球蛋白作用的替代方法，我们研究了激活诱导脱氨酶 (Aicda-/-) 基因缺失的小鼠。这些小鼠 IgM 水平升高，但几乎没有 IgG 亚类和 IgA 等类别转换免疫球蛋白。雄性和雌性 Aicda-/-小鼠均不能预防 Ang II 诱导的高血压和肾脏/血管损伤。为了确定 IgM 或 B 细胞的非免疫球蛋白依赖性先天功能是否在高血压中起作用，我们研究了由于 IgM 重链膜外显子缺失而导致严重全身性 B 细胞缺乏的小鼠（µMT-/-）。µMT-/-小鼠也不能预防 Ang II 输注或地塞米松-醋酸盐盐处理引起的高血压或靶器官损伤。
这些结果表明 B 细胞和血清免疫球蛋白在高血压病理中不起因果作用。
