New and innovative treatments for autoimmune diseases could soon be tested after a mechanism involved in their development was identified by German researchers.
The hope follows the discovery that the development and functioning of regulatory T cells, also known as Tregs, and T helper 17 (TH17) cells, can be influenced by inhibiting the protein kinase CK2.
Writing in the Proceedings of the National Academy of Sciences, the team says that many of the effects of autoimmune disorders appear to be attributable to TH17 cells. The relative levels of these two types of cells determine whether or not an autoimmune disorder develops.
The team, from the Research Centre for Immunotherapy (FZI) and the Focus Program Translational Neurosciences (FTN) of Johannes Gutenberg University Mainz (JGU), inhibited the development of the auto-aggressive TH17 cells by blockading CK2 and simultaneously promoting the synthesis of Tregs.
The T-cells identify invading pathogens on the basis of their proteins and normally orchestrate a qualitative and quantitative defensive immune reaction, neutralising and eliminating the external invaders.
Occasionally, this defensive reaction causes an exaggerated immune response, which is why Tregs have evolved to help prevent that occurring.
Tregs protect harmless antigens such as foreign proteins in food that might otherwise trigger an endogenous defensive reaction, as well as the body’s own structures in the case of inappropriately activated immune responses. They also prevent the development of allergies and autoimmune disorders, including multiple sclerosis (MS).
Interleukin-(IL)17 producing TH17 cells – a sub-population of T helper cells – play a major role in the development of MS.
While in healthy people, TH17 cells control infecting bacteria and fungi, the cells are also responsible for the destructive processes that occur in the presence of inflammations and also in many autoimmune conditions.
The researchers have now found that it is not only the ratio of Tregs to TH17 cells that determines if an autoimmune disorder develops but also that pharmacological inhibition of CK2 tips the balance of the two cell types towards Tregs.
They found that restricting the protein kinase CK2 results in a blockade of the signal pathways that TH17 cells need to evolve.
Inhibiting the protein kinase CK2 leads to inhibition of the signal pathways mediated by the cytokines interleukin-6, interleukin-21, and interleukin-23 as well as those that regulate gene expression through the transcription factor STAT3.
This leads to the expression of another transcription factor, forkhead-box protein P3 (FOXP3), which in its turn controls the development and functioning of Tregs by genetic regulation, which means that auto-aggressive TH17 cells that are involved in the development of autoimmune diseases.
Professor Tobias Bopp at the Institute of Immunology at the Mainz University Medical Centre and Professor Frauke Zipp at the Department of Neurology headed the research.
Ulges A, Witsch E J, Pramanik G et al. Protein kinase CK2 governs the molecular decision between encephalitogenic TH17 cell and Treg cell development. Proc Natl Acad Sci 6 September 2016; doi: 10.1073/pnas.1523869113 [abstract]
Leave a Reply