Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695011, India.
Exp Biol Med (Maywood). 2019 Aug;244(11):893-900. doi: 10.1177/1535370219855002.
Variation in ligand-binding affinity of natural plasma anti-α-galactoside antibody (anti-Gal) is a plausible reason for differing anti-cancer defense among individuals since serine- and threonine-rich peptide sequences (STPS) in the cancer-specific MUC-1 antigen are surrogate ligands for this antibody. As affinity of a natural antibody could be modulated by systemic antigens by processes including affinity maturation, we examined the contribution of the size of lipoprotein(a) [Lp(a)], an efficient autologous anti-Gal-binding macromolecule that possesses variable numbers of STPS due to genetically determined size polymorphism, towards the specific activity (activity per unit mass) of anti-Gal. Binding of purified Lp(a) to FITC-labeled anti-Gal, measured in terms of increase in fluorescence of the latter, was inhibited by LDL in proportion to Lp(a) size presumably because LDL molecules also bind noncovalently and in proportion to Lp(a) size at the O-glycosylated and STPS-rich region of Lp(a). For the same reason, circulating forms of smaller Lp(a) which carried fewer or no noncovalently attached LDL molecules were more efficient ligands for the antibody than the same number of larger ones ( < 0.0001). Result suggested that smaller Lp(a), with their STPS ligands less obstructed by adhering LDL, would be more effective systemic antigens for anti-Gal. In confirmation of this, the specific activity of anti-Gal decreased with Lp(a) size (r − 0.5443; < 0.0001) but increased with Lp(a) concentration (r 0.6202; < 0.0001) among 73 normal plasma samples. IgG to IgM ratio, an index of immunoglobulin class switching characteristic of affinity maturation, was decidedly higher for anti-Gal in small Lp(a) individuals than in their large Lp(a) counterparts ( = 0.0014). Results indicated that modulation of activity of anti-Gal by Lp(a) size may account for the lower incidence of cancer reported in people carrying more plasma Lp(a) which are generally smaller as well.
天然血浆抗α-半乳糖苷抗体（抗-Gal）的配体结合亲和力的变化是个体间抗癌防御能力不同的一个合理原因，因为在肿瘤特异性 MUC-1 抗原中富含丝氨酸和苏氨酸的肽序列（STPS）是该抗体的替代配体。由于包括亲和力成熟在内的过程，天然抗体的亲和力可以被系统抗原调节，因此我们研究了脂蛋白（a）[Lp（a）]的大小对抗-Gal 特异性活性（单位质量的活性）的贡献，Lp（a）是一种有效的自体抗-Gal 结合大分子，由于遗传决定的大小多态性，它具有可变数量的 STPS。用 FITC 标记的抗-Gal 测量的纯化 Lp（a）与 LDL 的结合，以后者荧光的增加为指标，与 Lp（a）的大小成比例被抑制，推测是因为 LDL 分子也以非共价方式结合，并且与 Lp（a）的大小成比例在 Lp（a）的 O-糖基化和 STPS 丰富区域。由于同样的原因，携带较少或没有非共价附着 LDL 分子的较小 Lp（a）的循环形式比相同数量的较大 Lp（a）更有效地作为抗体的配体（<0.0001）。结果表明，较小的 Lp（a），其 STPS 配体较少受到粘附 LDL 的阻碍，将成为更有效的抗-Gal 系统抗原。为了证实这一点，在 73 份正常血浆样本中，抗-Gal 的特异性活性随 Lp（a）的大小而降低（r-0.5443；<0.0001），但随 Lp（a）浓度而增加（r0.6202；<0.0001）。IgG 到 IgM 的比值，是亲和力成熟特征的免疫球蛋白类别转换的指标，在小 Lp（a）个体的抗-Gal 中明显高于大 Lp（a）个体（=0.0014）。结果表明，Lp（a）大小对抗-Gal 活性的调节可能解释了携带更多通常较小的血浆 Lp（a）的人报告的癌症发病率较低的原因。
