Autoreactive antibodies control blood

The random nature of antibody repertoire generation includes the potential for production of autoantibodies recognizing self-structures. It is believed that the establishment of immunological tolerance and the prevention of autoimmune diseases require the suppression of recognizing antibody specificities.

Using insulin as a common and physiologically important autoantigen, we show that anti-insulin antibodies associated with autoimmune diabetes can be readily detected in mice and humans and are involved in the physiological regulation of blood glucose.

Importantly, high affinity human anti-insulin IgM antibodies protect insulin from autoimmune degradation by anti-insulin IgG antibodies. Thus, unlike the proposed negative selection, self-recognition and the production of highly autoreactive IgM antibodies are important for the induction of tolerance.

Metabolic homeostasis through hormone production is crucial for maintaining physiological integrity, as an imbalance can cause serious metabolic disorders such as diabetes mellitus. Here we show that antibody-deficient mice and immunocompromised patients have subphysiological blood glucose concentrations.

Restoration of glycemic physiology required injections of total IgG 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 have identified two fractions of anti-insulin IgM in the serum of healthy individuals.

These autoreactive IgM fractions differ in their affinity for insulin. Interestingly, the low affinity IgM fraction (anti-insulin IgMlow) neutralizes insulin and leads to an increase in blood sugar, while the high-affinity IgM fraction (anti-insulin IgMhigh) protects insulin from neutralization by insulin. anti-insulin IgG, thereby preventing blood sugar dysregulation.

To demonstrate that anti-insulin IgMhigh acts as an insulin protector and counteracts the neutralization of insulin by anti-insulin IgG, we expressed the variable regions of a high-affinity anti-insulin antibody in IgG and IgM. Remarkably, the recombinant anti-insulin IgMhigh normalized insulin function and prevented IgG-mediated insulin neutralization.

These results suggest that autoreactive insulin-recognizing antibodies are key regulators of blood sugar and metabolism, as they control the concentration of insulin in the blood. Moreover, our data suggest that prevention of autoimmune damage and maintenance of physiological homeostasis require adaptive tolerance mechanisms generating high-affinity autoreactive IgM antibodies during memory responses.