Tn-reactive immunoglobulin M (IgM) might form the first line of defense against SARS-CoV-2 infection (COVID-19): A proposed immunobiological background

The anti-Tn-reactive immunoglobulin M (IgM) might be identical to the nonimmune, germline-encoded blood group A-reactive isoagglutinin, expressed by the ancient poly- and autoreactive germline-encoded immunoglobulin M (IgM) in humans, which is serologically identical to anti-A from the C57BL/10 mouse and hardly arises in response to A-allelic genetic activities. This antibody, which does not occur in sera from blood group A individuals, may reflect the functions of metazoan defense proteins or lectins, which are considered non-self/self-recognition molecules that monitor expression of the cross-species evolutionary serological Tn antigen (<em>O</em>-GalNAcα1-Ser/Thr-R). Tn (T nouvelle) is an intermediate structure, almost exclusively expressed in tumor tissues and represents a key point of non-self-/self-recognition in metazoan species, while its complementary protein in human plasma, the anti-Tn-reactive IgM, mediates growth process monitoring. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the human body via a trans-species Tn formation. The viral serine molecule, mobilized from the viral spike (S) protein by the host transmembrane protease serine subtype 2 (TMPRSS2) enzyme, was identified as a fusion molecule, essential for SARS-CoV-2 infection, wherein the syngeneic serine might be replaced by the pathogen molecule and the key point of nonself/self-recognition become the target of infection and source of aggressive autoimmunization. While it was argued that anti-Tn is protective against SARS-CoV-2, the hypothetical, cross-species enzyme-substrate competition between the host and viral serine molecule occurs preferentially in blood group A and the other non-O blood groups, whereas in blood group O(H), the foreignness of the hybrid Tn epitope is recognized as non-self by the corresponding anti-Tn-reactive IgM, which in concert with secondary anti-Tn-reactive immunoglobulin G (IgG) forms the first line of defense. <br>

抗Tn反应性免疫球蛋白M（IgM）可能与天然生殖系编码的A血型反应性同种凝集素完全一致，后者由人体内古老的多反应性及自身反应性生殖系编码免疫球蛋白M（IgM）表达，其血清学特征与C57BL/10小鼠来源的抗A抗体一致，且几乎不会因A等位基因的遗传活性而产生。该抗体不存在于A血型个体的血清中，其功能或可反映多细胞动物防御蛋白或凝集素的作用——这类分子被视为非己/己识别分子，可监测跨物种进化血清学Tn抗原（O-GalNAcα1-Ser/Thr-R）的表达。Tn（T nouvelle，即新T抗原）是一种中间结构，几乎仅在肿瘤组织中表达，是多细胞动物中非己/己识别的关键节点；而人血浆中与其互补的抗Tn反应性IgM，则介导生长过程监测。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）可通过跨物种Tn结构形成入侵人体。经宿主跨膜丝氨酸蛋白酶2（TMPRSS2）从病毒刺突（S）蛋白上解离的病毒丝氨酸分子，被证实为SARS-CoV-2感染所必需的融合分子。在此过程中，同源丝氨酸可被病原体分子替代，而非己/己识别的关键节点便成为感染的靶点及侵袭性自身免疫反应的诱因。尽管有观点认为抗Tn对SARS-CoV-2具有防护作用，但宿主与病毒丝氨酸分子间假设存在的跨物种酶-底物竞争，优先发生于A型血及其他非O型血人群中；而在O(H)血型人群中，杂合Tn表位的异源性会被相应的抗Tn反应性IgM识别为非己，该抗体与继发性抗Tn反应性免疫球蛋白G（IgG）协同构成第一道免疫防线。