Antibodies control metabolism by regulating insulin homeostasis

Abstract

Homeostasis of metabolism by hormone production is crucial to maintain physiological integrity and disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibodies recognizing insulin are key regulators of blood glucose and metabolism controlling insulin concentrations. In fact, antibody-deficient mice and immunodeficiency patients show sub-physiological blood glucose, which becomes normal after total IgG injection. We show that insulin-specific IgG antibodies found in the serum of wildtype mice or healthy individuals are responsible for this regulation. Interestingly, we identify two fractions of anti-insulin IgM which differ in their affinity to insulin. The low affinity IgM fraction (anti-insulin IgMlow) neutralizes insulin and leads to increased blood glucose while the high affinity IgM fraction (anti-insulin IgMhigh) protects insulin from neutralization by anti-insulin IgG thereby preventing blood glucose dysregulation. In contrast to anti-insulin IgMhigh, anti-insulin IgMlow binds to dsDNA suggesting that it is multi-specific. This multi-specificity mediates the formation of larger immune complexes containing insulin which results in increased uptake and degradation of insulin by macrophages in the presence of anti-insulin IgMlow as compared to anti-insulin IgMhigh. To demonstrate that high affinity anti-insulin IgM acts as protector of insulin and counteracts insulin neutralization by anti-insulin IgG, we expressed the variable regions of the same anti-insulin antibody as IgG or IgM. Strikingly, only the anti-insulin IgM regulated insulin function and prevented IgG-mediated neutralization of insulin and subsequent blood glucose dysregulation. Since anti-insulin IgMhigh is generated in the course of an immune response and affinity maturation, its protective role suggests that preventing autoimmune damage and maintaining physiological homeostasis requires adaptive tolerance mechanisms that generate protective IgM antibodies during memory responses.

Rheumatoid factor IgM autoantibodies control IgG homeostasis

“…In full agreement, our recent work showed that blood glucose levels are tightly regulated by insulin-specific autoantibodies of the IgM and IgG class (17,18). In particular, we demonstrated that insulin-specific IgG neutralizes circulating insulin in wild-type (WT) mice, while PR-IgM autoantibodies with high specificity and affinity for insulin, generated in the course of secondary immune responses, play a protective role on circulating insulin by preventing IgG-induced insulin degradation.…”

“…To confirm our hypothesis that IgM affinity and specificity determines the outcome of the interaction with the recognized cognate antigen, we used recombinant anti-insulin antibodies as model. In our previous study, we cloned a monoclonal antiinsulin antibody and studied its effect on insulin function when expressed as IgG or IgM isotype (18). This monoclonal antibody has high affinity (K D 10 -9 ) to its target autoantigen and neutralized insulin when expressed as IgG, while expression as IgM protected insulin from IgG-mediated neutralization in vivo (18).…”

“…Therefore, self-recognition by a specific class of high affinity mono-specific IgM autoantibodies is important for selfprotection and prevention of autoimmune destruction (18). While this scenario is in contrast to the proposed general removal of autoreactive specificities, it suggests that unrestricted diversity is not only required for the elimination of potentially infinite pathogens but also for the specific protection of self by the generation of memory PR-IgM.…”

“…Though the presence of autoantibodies in normal healthy population has always been related to defective clearance of autoreactive specificities, there are evidences suggesting that autoantibodies are retained in circulation as they play a specific role in maintenance of physiological homeostasis (16,18,19,32,33,35,36).…”

“…In particular, we demonstrated that insulin-specific IgG neutralizes circulating insulin in wild-type (WT) mice, while PR-IgM autoantibodies with high specificity and affinity for insulin, generated in the course of secondary immune responses, play a protective role on circulating insulin by preventing IgG-induced insulin degradation. Conversely, primary insulin-specific IgM antibodies (primary IgM, pIgM) which are polyreactive and possess low affinity for insulin, lead to target destruction and thus to higher blood glucose levels (16)(17)(18).…”