Kyaw Tin, Tay Christopher, Khan Abdul, Dumouchel Vanessa, Cao Anh, To Kelly, Kehry Merilyn, Dunn Robert, Agrotis Alex, Tipping Peter, Bobik Alex, Toh Ban-Hock
Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Research Institute, Victoria, Australia.
J Immunol. 2010 Oct 1;185(7):4410-9. doi: 10.4049/jimmunol.1000033. Epub 2010 Sep 3.
Atherosclerosis is a chronic inflammatory arterial disease characterized by focal accumulation of lipid and inflammatory cells. It is the number one cause of deaths in the Western world because of its complications of heart attacks and strokes. Statins are effective in only approximately one third of patients, underscoring the urgent need for additional therapies. B cells that accumulate in atherosclerotic lesions and the aortic adventitia of humans and mice are considered to protect against atherosclerosis development. Unexpectedly, we found that selective B cell depletion in apolipoprotein E-deficient (ApoE(-/-)) mice using a well-characterized mAb to mouse CD20 reduced atherosclerosis development and progression without affecting the hyperlipidemia imposed by a high-fat diet. Adoptive transfer of 5 × 10(6) or 5 × 10(7) conventional B2 B cells but not 5 × 10(6) B1 B cells to a lymphocyte-deficient ApoE(-/-) Rag-2(-/-) common cytokine receptor γ-chain-deficient mouse that was fed a high-fat diet augmented atherosclerosis by 72%. Transfer of 5 × 10(6) B2 B cells to an ApoE(-/-) mouse deficient only in B cells aggravated atherosclerosis by >300%. Our findings provide compelling evidence for the hitherto unrecognized proatherogenic role of conventional B2 cells. The data indicate that B2 cells can potently promote atherosclerosis development entirely on their own in the total absence of all other lymphocyte populations. Additionally, these B2 cells can also significantly augment atherosclerosis development in the presence of T cells and all other lymphocyte populations. Our findings raise the prospect of B cell depletion as a therapeutic approach to inhibit atherosclerosis development and progression in humans.
动脉粥样硬化是一种慢性炎症性动脉疾病，其特征是脂质和炎症细胞的局灶性积聚。由于其引发心脏病发作和中风的并发症，它是西方世界头号死因。他汀类药物仅对约三分之一的患者有效，这凸显了对其他治疗方法的迫切需求。在人类和小鼠的动脉粥样硬化病变及主动脉外膜中积聚的B细胞被认为可预防动脉粥样硬化的发展。出乎意料的是，我们发现使用一种针对小鼠CD20的特性明确的单克隆抗体，在载脂蛋白E缺陷（ApoE(-/-)）小鼠中选择性清除B细胞，可减少动脉粥样硬化的发展和进展，而不影响高脂饮食导致的高脂血症。将5×10⁶或5×10⁷个传统B2 B细胞而非5×10⁶个B1 B细胞过继转移到喂食高脂饮食的淋巴细胞缺陷型ApoE(-/-) Rag-2(-/-) 共同细胞因子受体γ链缺陷小鼠中，可使动脉粥样硬化增加72%。将5×10⁶个B2 B细胞转移到仅B细胞缺陷的ApoE(-/-)小鼠中，会使动脉粥样硬化加重>300%。我们的研究结果为传统B2细胞迄今未被认识的促动脉粥样硬化作用提供了令人信服的证据。数据表明，在完全没有所有其他淋巴细胞群体的情况下，B2细胞自身就能有力地促进动脉粥样硬化的发展。此外，在存在T细胞和所有其他淋巴细胞群体的情况下，这些B2细胞也能显著增强动脉粥样硬化的发展。我们的研究结果提出了清除B细胞作为一种治疗方法来抑制人类动脉粥样硬化发展和进展的前景。
