The enormous diversity of antibody specificities is generated by random rearrangement of immunoglobulin gene segments and is important for general protection against pathogens. Since random rearrangement harbors the risk of producing self-destructive antibodies, it is assumed that autoreactive antibody specificities are removed during early B-cell development leading to a peripheral compartment devoid of autoreactivity. Here, we immunized wild-type mice with insulin as a common self-antigen and monitored diabetes symptoms as a measure for autoimmune disease. Our results show that autoreactive anti-insulin IgM and IgG antibodies associated with autoimmune diabetes can readily be generated in wild-type animals. Surprisingly, recall immunizations induced increased titers of high-affinity insulin-specific IgM, which prevented autoimmune diabetes. We refer to this phenomenon as adaptive tolerance, in which high-affinity memory IgM prevents autoimmune destruction by competing with self-destructive antibodies. Together, this study suggests that B-cell tolerance is not defined by the absolute elimination of autoreactive specificities, as harmful autoantibody responses can be generated in wild-type animals. In contrast, inducible generation of autoantigen-specific affinity-matured IgM acts as a protective mechanism preventing self-destruction.

中文翻译：

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记忆 IgM 保护内源性胰岛素免受自身免疫破坏


抗体特异性的巨大多样性是由免疫球蛋白基因片段的随机重排产生的，对于针对病原体的一般保护非常重要。由于随机重排存在产生自毁性抗体的风险，因此假设自身反应性抗体特异性在早期 B 细胞发育过程中被消除，导致外周区室缺乏自身反应性。在这里，我们用胰岛素作为常见自身抗原对野生型小鼠进行免疫，并监测糖尿病症状作为自身免疫性疾病的衡量标准。我们的结果表明，与自身免疫性糖尿病相关的自身反应性抗胰岛素 IgM 和 IgG 抗体很容易在野生型动物中产生。令人惊讶的是，回忆免疫诱导高亲和力胰岛素特异性 IgM 滴度增加，从而预防自身免疫性糖尿病。我们将这种现象称为适应性耐受，其中高亲和力记忆 IgM 通过与自我破坏性抗体竞争来防止自身免疫破坏。总之，这项研究表明，B 细胞耐受性并不是通过绝对消除自身反应特异性来定义的，因为野生型动物中可能会产生有害的自身抗体反应。相比之下，自身抗原特异性亲和力成熟 IgM 的诱导生成起到了防止自我毁灭的保护机制的作用。