Dysregulation of autoreactive B cell responses in autoimmune diseases: from initial triggering to persistent activation

Abstract

B cells play an important role in the human immune system by providing protection against pathogens. The response of B cells to pathogens is tightly regulated to ensure an effective immune response is generated. When this strict regulation is lost, B cell responses against structures of the human body can arise. These B cells that recognize self-proteins, termed autoreactive B cells, play an important role in the pathogenesis of autoimmune diseases. The research presented in this thesis focuses on unraveling the mechanisms underlying the development, dynamics, and role of autoreactive B cell responses in autoimmune diseases. By characterizing autoreactive B cells, this thesis describes that autoreactive B cells are highly activated in the autoimmune diseases rheumatoid arthritis and systemic sclerosis. In systemic sclerosis, it was found that DNA binding by the self-molecule recognized by autoreactive B cells enhances the activation of these cells. In addition, autoreactive B cells were found to be activated by antigen derived from microbes. These findings contribute to a better understanding of the dysregulation of autoreactive B cells in rheumatic autoimmune diseases. Silencing or depleting these activated autoreactive B cell responses may be required to effectively treat and, potentially, cure human autoimmune diseases.