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小鼠实施精准时序的卵巢切除术（ovariectomy），首次实验证实了哺乳动物中非免疫性免疫球蛋白M（IgM，immunoglobulin M）分子的种系编码（germline encoding）特性。这类天然抗体的靶标为一种跨物种发育抗原，该抗原若在非发育组织中表达则可提示恶性病变。尽管卵巢切除术与阉割术（castration）可引发失控或增强的体液免疫与细胞免疫反应，表现为脾脏与胸腺重量增加，且B细胞、T细胞生成显著增多，但在青春期前对C57BL/10小鼠实施卵巢切除术后，其血浆中对巯基乙醇敏感、具备补体结合能力的非免疫性抗A反应性并未得到增强。这种非免疫性小鼠抗A抗体可与同系卵巢携带N-乙酰半乳糖胺（GalNAc）聚糖的糖脂（glycolipids）互补，且与交叉反应性适应性抗A抗体截然不同；若在小鼠20日龄时实施卵巢切除术，其血浆中的这类抗A反应会显著下调或完全消失。因此，与我们此前的认知相悖，该抗A反应不太可能源自体细胞、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，且通过与天然人源抗A抗体反应，在雌雄生殖器官与内胚层器官（endodermal organs）中进一步鉴定出了类A结构；而小鼠抗A反应仅可被同系卵巢糖脂所抑制。此外，作为进化与发育终末位点之一的早期卵巢组织，呈现出以双花扁豆（Dolichos biflorus）凝集素与园蜗牛（Helix pomatia）凝集素反应为特征的发育多态性，这表明O-连接N-乙酰半乳糖胺（O-GalNAc）决定的粘蛋白型类A、Tn及汤姆森-弗里德里希（Thomsen-Friedenreich, TF）表位，在非发育组织中蓄积并表达时可提示恶性病变。