Caligiuri Giuseppina, Nicoletti Antonino, Poirier Bruno, Hansson Göran K
Center for Molecular Medicine and Department of Medicine, Karolinska Institute, SE-171 76 Stockholm, Sweden.
J Clin Invest. 2002 Mar;109(6):745-53. doi: 10.1172/JCI7272.
Atherosclerosis is characterized by vascular inflammation and associated with systemic and local immune responses to oxidized LDL (oxLDL) and other antigens. Since immunization with oxLDL reduces atherosclerosis, we hypothesized that the disease might be associated with development of protective immunity. Here we show that spleen-associated immune activity protects against atherosclerosis. Splenectomy dramatically aggravated atherosclerosis in hypercholesterolemic apoE knockout (apoE degrees ) mice. Transfer of spleen cells from atherosclerotic apoE degrees mice significantly reduced disease development in young apoE degrees mice. To identify the protective subset, donor spleen cells were divided into B and T cells by immunomagnetic separation before transfer. Protection was conferred by B cells, which reduced disease in splenectomized apoE degrees mice to one-fourth of that in splenectomized apoE degrees controls. Protection could also be demonstrated in intact, nonsplenectomized mice and was associated with an increase in antibody titers to oxLDL. Fewer CD4(+) T cells were found in lesions of protected mice, suggesting a role for T-B cell cooperation. These results demonstrate that B cell-associated protective immunity develops during atherosclerosis and reduces disease progression.
动脉粥样硬化的特征是血管炎症，并与对氧化低密度脂蛋白（oxLDL）和其他抗原的全身及局部免疫反应相关。由于用oxLDL免疫可减轻动脉粥样硬化，我们推测该疾病可能与保护性免疫的发展有关。在此我们表明，脾脏相关免疫活性可预防动脉粥样硬化。脾切除术显著加重了高胆固醇血症载脂蛋白E基因敲除（apoE−/−）小鼠的动脉粥样硬化。将动脉粥样硬化apoE−/−小鼠的脾细胞转移到年轻的apoE−/−小鼠中，可显著减少疾病发展。为了确定保护性亚群，在转移前通过免疫磁珠分离将供体脾细胞分为B细胞和T细胞。B细胞赋予了保护作用，其将脾切除的apoE−/−小鼠的疾病减轻至脾切除的apoE−/−对照小鼠的四分之一。在完整的、未进行脾切除的小鼠中也可证明有保护作用，且这与抗oxLDL抗体滴度的增加有关。在受保护小鼠的病变中发现的CD4(+) T细胞较少，提示T细胞与B细胞合作发挥了作用。这些结果表明，与B细胞相关的保护性免疫在动脉粥样硬化过程中发展，并减少疾病进展。
