Binder Christoph J, Hörkkö Sohvi, Dewan Asheesh, Chang Mi-Kyung, Kieu Emily P, Goodyear Carl S, Shaw Peter X, Palinski Wulf, Witztum Joseph L, Silverman Gregg J
Divisions of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0682 USA.
Nat Med. 2003 Jun;9(6):736-43. doi: 10.1038/nm876. Epub 2003 May 12.
During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.
在动脉粥样硬化进展过程中，会诱导产生针对氧化型低密度脂蛋白（oxLDL）表位的自身抗体，用oxLDL对高胆固醇血症小鼠进行主动免疫可改善动脉粥样硬化的发生。我们意外地发现，许多源自“未接触过抗原的”动脉粥样硬化小鼠的抗oxLDL自身抗体与经典抗磷酸胆碱B细胞克隆T15产生的抗体具有完全相同的基因和结构，T15抗体可抵御包括肺炎球菌在内的常见感染性病原体。为了研究体内接触肺炎球菌是否会影响动脉粥样硬化的发生，我们用肺炎链球菌免疫Ldlr(-/-)小鼠。这诱导了循环中高水平的oxLDL特异性IgM以及主要在脾脏中持续扩增的分泌oxLDL特异性T15 IgM的B细胞，这些B细胞与肺炎球菌决定簇具有交叉反应性。肺炎球菌免疫降低了动脉粥样硬化的程度，并且这些小鼠的血浆阻断oxLDL与巨噬细胞结合的能力增强。这些研究表明oxLDL和肺炎链球菌的表位之间存在分子模拟，并表明这些免疫反应可能具有有益作用。
