After blood transfusion patients regularly form antibodies against donor blood cells (alloantibodies). This causes undesired side effects and becomes a major problem when donors need to receive multiple transfusions. Alloimmunisation occurs through activation of B cells by parts of the donor blood cells. After this, the B cells start to divide and eventually change into plasma cells that secrete such alloantibodies for decades. Currently, there are no good therapies that can destroy these plasma cells once they are formed. Preventing formation of these undesired plasma cells in donors would therefore be a major step forward. For this we need to be able to 1) analyse B cells when they become activated and change before they turn into these plasma cells and 2) define a therapy that can stop these activated B cells from becoming plasma cells. In this project we succeeded in setting up assays in the laboratory in which we can activate B cells and study large numbers of the different stage of B cell change before they form plasma cells. Now that we set up this assay, we identified novel regulating proteins and novel markers that control or mark the early B cell stages. We demonstrated that B cells go through different stages and have specific markers. We were also able to stop or enhance formation of plasma cells by targeting molecules that are involved in this process (CD40, IL-21, IL-4 and STAT3). The outcome of this process now allows us to investigate if these early markers can identify B cells before they become undesired antibody-secreting plasma cells in patients and if we can prevent this process in patients in future. The project may thus prevent alloimmunisation in future and will improve patient care, efficacy and safety of transfusion therapy. In addition, the knowledge of this project may also be used to enhance plasma cell formation to improve vaccination protocols against current or emerging pathogens and to optimize hyperimmunisation protocols of Sanquin to generate much needed specific human immunoglobulins in voluntary donors.

THESIS 2023: Regulation of human B cell differentiation - Casper Marsman