B cell subsets in autoimmune disease

Abstract: B lymphocytes are a type of white blood cells, belonging to the adaptive arm of the immune system and involved in creating immunological memory. B cells function in the humoral immune system by secreting antibodies which can bind pathogens to prevent them from doing further damage and to help other immune cells to target them. It is highly important that the immune system can distinguish self from none-self, since an immune response to self-antigens would cause the immune system to attack the hosts own healthy cells and tissues. The development of different B cells subsets is highly complex and both differentiation and proliferation is under strict transcriptional control. Defects in lymphopoiesis can lead to serious disorders like immunodeficiency, allergy, malignancy and autoimmunity. In Study I we wanted to create a B1 cell-deficient mouse model by deleting the transcription factor Arid3a in a B cell-dependent manner. B1 cells are known to secrete natural antibodies which have shown to be atheroprotective and play other important roles in pathogenic conditions and diseases affecting a large number of people in the world. Our results demonstrate that Arid3a is required for specific immune responses and for the generation of normal cell numbers in a subset-dependent manner. In Study II we were interested in understanding the function of germinal center formation in rheumatoid arthritis. We wanted to explain the involvement of antibody production and to target germinal center B cells, highly involved in the development and progression of this disease. Our results show that germinal center B cells are essential for experimental arthritis and targeting them could help when establishing more refined B cell-depleting therapeutics for clinical arthritis. In Study III we wanted to understand the role of the adaptive immune system throughout the disease course of multiple sclerosis. B lymphocytes are known to be highly involved in influencing this disease, however the role of germinal center B cells has been unknown. To illuminate the function of germinal center responses, we induced experimental autoimmune encephalomyelitis in a murine model lacking germinal centers. We show that the functions of germinal center B cells is antigen-dependent and can both protect and promote disease. In Study IV we deleted Apoe in a novel atherosclerotic murine model, in order to induce acute hypercholesterolemia in adult mice. Currently, there exists various atherosclerotic mouse models, however atherosclerosis differs between human and mouse and therefore we were interested in interrogating this disease in an inducible murine model. Our results demonstrate that the acute loss of Apoe triggers an autoimmune response, accelerating atherosclerosis.