A new immunological model from Ulm, Germany could trigger a paradigm shift in the treatment of autoimmune diseases. In the EMBO Journal, researchers led by Prof. Hassan Jumaa describe the previously unknown mechanism of "adaptive tolerance". According to this, autoreactive antibodies are by no means harmful and should be eliminated as quickly as possible by the organism. Rather, they trigger the formation of so-called igM antibodies, which avert physical damage. Applications of this dynamic immunological model range from the development of new diabetes therapies to vaccine research.
Immunologists at Ulm University Hospital have developed a novel model that could revolutionise the treatment of autoimmune diseases or vaccine development. According to "adaptive tolerance", autoreactive antibodies are by no means disease drivers that the healthy organism eliminates early on. Rather, they trigger the formation of an antibody class that protects the body's own structures. The Ulm researchers led by Professor Hassan Jumaa first described this paradigm shift in the renowned EMBO Journal.
Autoimmune diseases are widespread in industrialised countries: Around 5% of the population suffers from diseases such as type 1 diabetes or rheumatism, in which the immune defence is directed against the body's own structures. Until now, autoreactive antibodies, which are normally identified and removed during early B cell development, were considered to be the disease drivers. As a reminder, B cells are a crucial component of the adaptive immune system and can trigger the formation of pathogen-specific antibodies.
Now, researchers led by Professor Hassan Jumaa, head of the Ulm Institute of Immunology, have investigated and ultimately redefined the role of different autoreactive antibodies.
The research project focused on immunisation experiments in the mouse model. The healthy animals received human insulin in the form of protein complexes as an autoantigen. The hormone insulin is important for metabolism: Diabetics are treated for insulin deficiency.
"The mice were closely examined for defence reactions using methods from diabetology. In the process, we discovered autoreactive and thus harmful antibodies that, according to previous assumptions, should have been eliminated long ago in healthy mice," explains Professor Jumaa. A previously widespread thesis on autoreactive antibodies was thus already disproved. In addition, the immunologists found that a renewed administration of the insulin-protein complexes caused the insulin-specific antibody titre in the mice to skyrocket. These immunoglobulin-M (igM) antibodies were able to slow down the previously detected autoimmune reaction and prevent physical damage in the mice. The researchers from Ulm call this previously unknown mechanism "adaptive tolerance".
"Contrary to earlier assumptions, our investigations show that a healthy defence reaction triggers the formation of protective IgM antibodies. This modulates the immune response and protects the body from autoreactive antibodies. According to this, a diverse B cell repertoire seems to be able to cushion harmful autoimmune reactions through adaptive IgM antibodies," is how first author Timm Amendt sums up the research results. Adaptive tolerance is thus based on the interplay of different autoantigen complexes. If this balancing act is upset, autoimmune diseases can develop. In a further study, which was recently published on a preprint server, the immunologists prove that these research results can be transferred from the mouse model to humans.
Overall, the paradigm shift from a static to a dynamic immunological model ("adaptive tolerance") provides unexpected insights into the development and treatment of autoimmune diseases. In the next step, the researchers around Professor Hassan Jumaa want to use the new model to investigate whether adaptive IgM antibodies can be used in the treatment or prevention of diabetes. Another area of application is, for example, vaccine development.
References:
1. Amendt T and Jumaa H (2021), Memory IgM protects endogenous insulin from autoimmune destruction, The EMBO Journal. https://www.embopress.org/doi/full/10.15252/embj.2020107621
2. Preprint study: Amendt T, Allies G, Nicolo A, El Ayoubi O, Young M, Roeszer T, Setz CS, Warnatz W, Jumaa H (2021), Antibodies control metabolism by regulating insulin homeostasis. https://www.biorxiv.org/content/10.1101/2021.08.10.455644v1