期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：6
DOI：10.1073/pnas.2115695119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The random nature of antibody repertoire generation includes the potential of producing autoantibodies recognizing self-structures. It is believed that establishing immunological tolerance and prevention of autoimmune diseases require the removal of antibody specificities recognizing self. Using insulin as a common and physiologically important autoantigen, we show that anti-insulin antibodies associated with autoimmune diabetes can readily be detected in mice and humans and are involved in the physiological regulation of blood glucose levels. Importantly, human high-affinity, anti-insulin IgM antibodies protect insulin from autoimmune degradation by anti-insulin IgG antibodies. Thus, in contrast to the proposed negative selection, self-recognition and the production of highly autoreactive IgM antibodies are important for tolerance induction.
Homeostasis of metabolism by hormone production is crucial for maintaining physiological integrity, as disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibody-deficient mice and immunodeficiency patients have subphysiological blood glucose concentrations. Restoring blood glucose physiology required total IgG injections and insulin-specific IgG antibodies detected in total IgG preparations and in the serum of healthy individuals. In addition to the insulin-neutralizing anti-insulin IgG, we identified two fractions of anti-insulin IgM in the serum of healthy individuals. These autoreactive IgM fractions differ in their affinity to insulin. Interestingly, the low-affinity IgM fraction (anti-insulin IgM
low) neutralizes insulin and leads to increased blood glucose, whereas the high-affinity IgM fraction (anti-insulin IgM
high) protects insulin from neutralization by anti-insulin IgG, thereby preventing blood glucose dysregulation. To demonstrate that anti-insulin IgM
high acts as a protector of insulin and counteracts insulin neutralization by anti-insulin IgG, we expressed the variable regions of a high-affinity anti-insulin antibody as IgG and IgM. Remarkably, the recombinant anti-insulin IgM
high normalized insulin function and prevented IgG-mediated insulin neutralization. These results suggest that autoreactive antibodies recognizing insulin are key regulators of blood glucose and metabolism, as they control the concentration of insulin in the blood. Moreover, our data suggest that preventing autoimmune damage and maintaining physiological homeostasis requires adaptive tolerance mechanisms generating high-affinity autoreactive IgM antibodies during memory responses.
