Robertson A-K L, Zhou X, Strandvik B, Hansson G K
Department of Medicine and Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Scand J Immunol. 2004 Mar;59(3):285-93. doi: 10.1111/j.0300-9475.2004.01403.x.
Severe hypercholesterolaemia is associated with decreased levels of immunoglobulin G2a (IgG2a) antibodies [T-helper 1 (Th1) response] to modified malondialdehyde-modified low-density lipoprotein (MDA-LDL) and increased levels of Th2-dependent IgG1 antibodies in apolipoprotein E-deficient (apoE(-/-)) mice. To investigate whether this reflects a general pattern of metabolic regulation of the humoral immune response, apoE(-/-) mice were fed diets resulting in different degrees of hypercholesterolaemia and immunized with keyhole limpet haemocyanin (KLH) in aluminium hydroxide. Cholesterol levels for different treatment groups ranged from 14 to 77 mmol/l in serum and from 10 to 39 mmol/g in liver. Mice with severe hypercholesterolaemia had increased IgG1 antibodies to MDA-LDL and decreased IgG2a anti-MDA-LDL. Importantly, titres of IgG2a antibodies to KLH were also decreased, while IgE anti-KLH was increased, with a corresponding induction of interleukin-4 (IL-4) and IL-10 and a decrease in interferon-gamma (IFN-gamma) in KLH-stimulated spleen cells in vitro. Thus, hypercholesterolaemia clearly affects antibody production both to the autoantigen MDA-LDL and to the exogenous antigen KLH, favouring antibody isotypes (IgG1 and IgE) that are dependent on Th2 help to B cells. Nuclear receptors ligated by oxidized lipid derivatives modulate T-cell responses, and it is speculated that this mechanism may cause the switch to Th2 in severe hypercholesterolaemia.
严重高胆固醇血症与载脂蛋白E缺陷（apoE(-/-)）小鼠中针对修饰的丙二醛修饰低密度脂蛋白（MDA-LDL）的免疫球蛋白G2a（IgG2a）抗体水平降低（T辅助细胞1（Th1）反应）以及Th2依赖性IgG1抗体水平升高有关。为了研究这是否反映了体液免疫反应代谢调节的一般模式，给apoE(-/-)小鼠喂食导致不同程度高胆固醇血症的饮食，并在氢氧化铝中用钥孔戚血蓝蛋白（KLH）进行免疫。不同治疗组的血清胆固醇水平在14至77 mmol/l之间，肝脏胆固醇水平在10至39 mmol/g之间。患有严重高胆固醇血症的小鼠针对MDA-LDL的IgG1抗体增加，而针对MDA-LDL的IgG2a抗体减少。重要的是，针对KLH的IgG2a抗体滴度也降低，而抗KLH的IgE增加，同时在体外KLH刺激的脾细胞中白细胞介素-4（IL-4）和IL-10相应诱导，干扰素-γ（IFN-γ）减少。因此，高胆固醇血症明显影响针对自身抗原MDA-LDL和外源性抗原KLH的抗体产生，有利于依赖Th2辅助B细胞的抗体亚型（IgG1和IgE）。由氧化脂质衍生物连接的核受体调节T细胞反应，推测这种机制可能导致严重高胆固醇血症时向Th2转变。
