Early ovariectomy reveals the germline encoding of the “natural” mammalian anti-A-reactive IgM reflecting developmental malignancy.

The germline encoding of a non-immune immunoglobulin M (IgM) molecule in mammals was experimentally documented for the first time as a result of the specifically timed ovariectomy of C57BL/10 mice. The target of this innate antibody involves a trans-species developmental antigen that signifies malignancy when expressed in any non-developmental tissue. Although ovariectomy and castration result in uncontrolled and/or enhanced humoral and cellular immunity involving increased weights of the spleen and thymus with pronounced B and T cell production, the development of mercaptoethanol-sensitive, complement-binding, non-immune anti-A reactivity in murine plasma was not enhanced after an ovariectomy that was performed in C57BL/10 mice prior to the onset of puberty. This non-immune murine anti-A, which is complementary to the trans-species, syngeneic ovarian GalNAc-glycan-bearing glycolipids and distinct from the cross-reactive adaptive anti-A antibody, was strongly downregulated or did not appear in plasma of animals ovariectomized at the age of 20 days. Thus, contrary to our previous view, this reactivity is unlikely to originate from a somatic, primary immune or autoimmune response. All of the murine tissues expressed the species-specific Forssman<i> </i>reactivity, and further A-like structures were identified in the male and female reproductive and endodermal organs by reaction with innate human anti-A antibody, while the murine anti-A was exclusively inhibited by syngeneic ovarian glycolipids. Moreover, the early ovarian tissue, which represents a last evolutionary and/or developmental location, showed a developmental polymorphism characterized by reactivity to the lectin from <i>Dolichos biflorus</i> and the agglutinin from <i>Helix pomatia </i>indicating the functional involvement of the <i>O</i>-GalNAc-determined mucin-type A-like, Tn- and Thomsen-Friedenreich (TF) epitopes that signify malignancy when accumulated and expressed in non-developmental tissues.

本研究通过对C57BL/10小鼠实施按特定时间窗设计的卵巢切除术，首次实验证实了哺乳动物体内非免疫性免疫球蛋白M（immunoglobulin M, IgM）分子的种系编码。该天然抗体的靶标为一类跨物种发育抗原，此类抗原在非发育组织中表达时可提示恶性病变。尽管卵巢切除术与阉割术可引发体液及细胞免疫的失控或增强，表现为脾、胸腺重量增加，B细胞与T细胞生成显著增多，但在青春期前对C57BL/10小鼠施行卵巢切除术后，小鼠血浆中巯基乙醇敏感、补体结合型的非免疫性抗A反应并未出现增强。这种与跨物种、同基因卵巢携带N-乙酰半乳糖胺聚糖的糖脂互补的非免疫性小鼠抗A活性物质，与交叉反应性适应性抗A抗体截然不同；在20日龄接受卵巢切除术的动物血浆中，该物质被显著下调，甚至无法检出。因此，与我们此前的认知相悖，该抗A反应不太可能起源于体细胞、原发性免疫或自身免疫应答。所有小鼠组织均表达物种特异性福斯曼（Forssman）反应性；通过与天然人源抗A抗体反应，在雌雄生殖器官及内胚层器官中还鉴定出了更多类A结构，而小鼠抗A反应仅可被同基因卵巢糖脂特异性抑制。此外，作为进化与发育的终末位点之一的早期卵巢组织，表现出以双花扁豆（Dolichos biflorus）凝集素和蜗牛（Helix pomatia）凝集素反应为特征的发育多态性，提示O-连接N-乙酰半乳糖胺决定的粘蛋白型类A、Tn及汤姆森-弗里德里希（Thomsen-Friedenreich, TF）表位发挥了功能性作用——这类表位在非发育组织中蓄积并异常表达时可提示恶性病变。