Memory IgM protects endogenous insulin from autoimmune destruction.
Timm AmendtHassan JumaaPublished in: The EMBO journal (2021)
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.
Keyphrases
- wild type
- type diabetes
- glycemic control
- multiple sclerosis
- drug induced
- cardiovascular disease
- insulin resistance
- working memory
- high glucose
- adipose tissue
- weight loss
- multidrug resistant
- metabolic syndrome
- mass spectrometry
- magnetic resonance imaging
- dna methylation
- skeletal muscle
- diabetic rats
- copy number
- mouse model
- depressive symptoms
- antimicrobial resistance
- endothelial cells