Cell Biology

An indication of how (rheumatic) chronic inflammation can initiate is provided by the severe disease course in COVID-19 patients who require intensive, prolonged medical care. In collaboration with the research group Mashreghi, we have studied the immune response of these patients over time. The early acute immune reaction induced by the SARS-CoV-2 virus is directed against the virus. However, later the immune reaction is no longer directed against the virus, rather against the patient’s own body. When memory lymphocytes are formed in this immune reaction, the inflammation becomes chronic, and it will no longer respond to therapies that suppress acute immune reactions.

Our group discovered some time ago memory plasma cells, which as we have shown in collaboration with the research group of Falk Hiepe, play a central role in chronic inflammations caused by antibodies, e.g. in systemic lupus erythematosus (SLE). Patients with such pathogenic memory plasma cells cannot achieve therapy-free remission, i.e. be cured, at best their disease symptoms can be suppressed.  These memory plasma cells are refractory to conventional therapies and continue to secrete their disease-driving antibodies undeterred. We are looking for novel approaches to target these cells therapeutically, from a basic understanding of how and where these cells survive in the body. We have shown that memory plasma cells are mainly located in the bone marrow and in inflamed tissues, where they attach to certain connective tissue cells. And we have shown that the plasma cells need contact with these stromal connective tissue cells to survive. Now we are deciphering the molecular code of the synapse between both cells, and how this translates into survival for different types of plasma cells, protective and pathogenic ones. For the first time, this may open up options for selectively eliminating pathogenic plasma cells, and ablating the cells causing chronic rheumatic inflammation driven by antibodies.

The precursors of memory plasma cells are memory B lymphocytes, which also control chronic inflammation themselves, together with memory T lymphocytes. Unexpectedly for the experts, we have now been able to show for the first time that most memory B lymphocytes, similar to memory plasma cells, are found in the bone marrow, where they also attach to connective tissue cells and do not circulate through the body via blood. We suspect that they are also maintained and survive in a similar way to plasma cells and are therefore resistant to conventional therapies. Even more surprising is that we could identify many different types of memory B lymphocytes. We are now investigating whether the pathogenic B lymphocytes in arthritis patients belong to a particular subset, which would enable us to target them selectively.

Together with memory B lymphocytes, memory T lymphocytes control immune reactions, especially the development of memory plasma cells, but also cytokine-mediated chronic inflammation, independent of antibodies. We were able to demonstrate this in Juvenile Idiopathic Arthritis (JIA): a type of arthritis affecting children. We detect these harmful memory T-lymphocytes mainly in the inflamed tissue itself, e.g. in the inflamed joints, where they actively control the chronic inflammation by secretion of cytokines, alarming other cells, and chemokines, attracting and activating effector cells. In order to survive in the joints, the memory T lymphocytes have to adapt to the inflammatory environment. We have identified genes that enable this adaptation, such as the transcription factor TWIST1 and the microRNA miR-148a. We could show that TWIST1 adapts the metabolism of the cells to the environment of the inflamed tissue and prevents death of the cells by switching on miR-148a, and antagonist of the pro-apoptotic gene BCL-2. In a mouse model of intestinal inflammation, we have already been able to selectively kill the harmful memory T lymphocytes in the animals, with “antagomirs” blocking mir-148a, without targeting protective memory T lymphocytes. This is the first indication that it is indeed possible to therapeutically ablate pathogenic memory T lymphocytes in a targeted manner.

Group leader
Prof. Dr. rer. nat Andreas Radbruch

Scientists
Jun Dong, PhD

PhD students
Xiangyi Deng
Lukas Heiberger
Jinchan Li
Pedram Mahmoudi
Emilia Schneider
Yu Shen
Zixu Wang