Investigating the multistep pathogenesis to autoimmune disease and cancer

© 2017 Dr. Antonia PolicheniIn the immune system, many immune checkpoints exist to prevent self-antigens from causing harm. Autoimmune disease arises in people that have defects in these critical checkpoints, despite complete defects in such mechanisms however, the latent phase that can be years to develop reveals the complex nature of immunological tolerance. The latency has been taken as evidence that defects must occur in several immune checkpoints, and studies in mice have confirmed that this is the case. The progression of cancer has also been shown to develop due to progressive defects in common immune checkpoints that are linked to autoimmune disease. Lymphoma develops in a latent nature, commonly due to accumulating somatic mutations in clones that bypass growth control mechanisms. This growth control ‘checkpoint’ that results in lymphoma, is also bypassed by autoreactive self-antigens that cause autoimmune disease; highlighting the common checkpoints that exist in the prevention of these two diseases. The similar stochastic nature of both cancer and autoimmune disease onset, has led us to investigate the stepwise defects that are required to cause both diseases. Advancing our understanding of immunology and autoimmunity, have led to considerable advances in the treatment of cancers with immunotherapy. It is now widely accepted that treating certain cancers with antibodies that target the negative regulators of the immune system in an attempt to ‘waken up’ the immune system is a new era to the way we view treatments. Inevitably through the manipulation of the immune system to treat cancer, these immune tolerance processes targeted will result in unfavorable immune pathology. Therefore a better understanding of the roles that these immune checkpoints play in both tolerance and cancer will help in the design of less toxic treatments. This thesis examines parallels in the processes governing the development of lymphocytes that escape quality control mechanisms and cause autoimmune disease or lymphoid cancer. We define common cellular and molecular checkpoints that can be subverted in autoimmunity and cancer. These studies highlight the importance of immune tolerance checkpoints in preventing disease progression, and offer new therapeutic targets in these pathologies