Pan Yue, Ke Hanzhong, Yan Zhaoqi, Geng Yajun, Asner Nathan, Palani Sunil, Munirathinam Gnanasekar, Dasari Subramanyam, Nitiss Karin C, Bliss Sarah, Patel Priyanka, Shen Hongming, Reardon Catherine A, Getz Godfrey S, Chen Aoshuang, Zheng Guoxing
Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA.
Department of Pathology (C.A.R., G.S.G.), University of Chicago, Chicago, IL 60637, USA.
Atherosclerosis. 2016 Aug;251:31-38. doi: 10.1016/j.atherosclerosis.2016.05.027. Epub 2016 May 19.
Anti-HMGB1 autoimmunity plays a role in systemic lupus erythematosus (SLE). Because SLE increases atherosclerosis, we asked whether the same autoimmunity might play a role in atherogenesis.
We looked for the induction of HMGB1-specific B and T cell responses by a western-type diet (WTD) in the Apoe(-/-) mouse model of atherosclerosis. We also determined whether modifying the responses modulates atherosclerosis.
In the plasma of male Apoe(-/-) mice fed WTD, the level of anti-HMGB1 antibodies (Abs) was detected at ∼50 μg/ml, which was ∼6 times higher than that in either Apoe(-/-) mice fed a normal chow or Apoe(+/+) mice fed WTD (p ≤ 0.0005). The Abs were directed largely toward a novel, dominant epitope of HMGB1 named HMW4; accordingly, compared with chow-fed mice, WTD-fed Apoe(-/-) mice had more activated HMW4-reactive B and T cells (p = 0.005 and p = 0.01, respectively). Compared with mock-immunized mice, Apoe(-/-) mice immunized with HMW4 along with an immunogenic adjuvant showed proportional increases in anti-HMW4 IgG and IgM Abs, HMW4-reactive B-1 and B-2 cells, and HMW4-reactive Treg and Teff cells, which was associated with ∼30% increase in aortic arch lesions (p ≤ 0.01) by two methods. In contrast, Apoe(-/-) mice immunized with HMW4 using a tolerogenic adjuvant showed preferential increases in anti-HMW4 IgM (over IgG) Abs, HMW4-reactive B-1 (over B-2) cells, and HMW4-specific Treg (over Teff) cells, which was associated with ∼40% decrease in aortic arch lesions (p ≤ 0.03).
Anti-HMGB1 autoimmunity may potentially play a role in atherogenesis.
抗高迁移率族蛋白B1（HMGB1）自身免疫在系统性红斑狼疮（SLE）中起作用。由于SLE会增加动脉粥样硬化的风险，我们探究这种自身免疫是否也在动脉粥样硬化的发生过程中发挥作用。
我们在动脉粥样硬化的载脂蛋白E基因敲除（Apoe(-/-)）小鼠模型中，研究西式饮食（WTD）是否会诱导产生针对HMGB1的特异性B细胞和T细胞反应。我们还确定调节这些反应是否会影响动脉粥样硬化的发展。
在喂食WTD的雄性Apoe(-/-)小鼠血浆中，抗HMGB1抗体（Abs）水平检测为~50μg/ml，这比喂食正常饲料的Apoe(-/-)小鼠或喂食WTD的Apoe(+/+)小鼠高出约6倍（p≤0.0005）。这些抗体主要针对HMGB1的一个新的、显性表位，名为HMW4；因此，与喂食普通饲料的小鼠相比，喂食WTD的Apoe(-/-)小鼠有更多活化的HMW4反应性B细胞和T细胞（分别为p = 0.005和p = 0.01）。与模拟免疫的小鼠相比，用HMW4和免疫原性佐剂免疫的Apoe(-/-)小鼠，其抗HMW4 IgG和IgM抗体、HMW4反应性B-1和B-2细胞以及HMW4反应性调节性T细胞（Treg）和效应性T细胞（Teff）均成比例增加，通过两种方法检测发现这与主动脉弓病变增加约30%相关（p≤0.01）。相反，用耐受性佐剂免疫HMW4的Apoe(-/-)小鼠，其抗HMW4 IgM（相对于IgG）抗体、HMW4反应性B-1（相对于B-2）细胞和HMW4特异性Treg（相对于Teff）细胞优先增加，这与主动脉弓病变减少约40%相关（p≤0.03）。
抗HMGB1自身免疫可能在动脉粥样硬化的发生中发挥作用。
