A systems approach to non-infectious uveitis

Abstract

Non-infectious uveitis (NIU) refers to a group of intraocular inflammatory conditions with great variability in disease course, visual prognosis, and treatment response. This inter-patient variability poses a challenge to find the right therapeutic approach for an individual patient. Also, as current therapies come with heavy side effects and fail to control NIU in up to 40% of all patients, there is a high need for new and more effective therapies. Ideally, such strategies will become more patient tailored (i.e. ‘personalized medicine’), taking clinical, personal, and molecular factors into account. To improve our understanding of this disease and pave the way for personalized medicine, we studied NIU using a systems approach, including clinical and molecular aspects as well as studying the personal impact of the disease on quality of life. In chapter 2 we studied the (peri) ocular pain and its impact on quality of life of non-infectious uveitis patients to better understand the impact of the disease. In chapters 3-5 we studied clinical as well as molecular aspects of HLA-B27 associated anterior uveitis in more detail. We studied the incidence and causes of permanent visual impairment and blindness caused by HLA-B27 associated anterior uveitis in chapter 3 and investigated the course of HLA-B27 associated acute anterior uveitis during pregnancy in chapter 4. In chapter 5, we studied the metabolic profiles of the aqueous humor (intraocular fluid) of patients with HLA-B27 positive and negative acute anterior uveitis in order to shed more light on the pathogenesis of the involvement of HLA-B27. To better understand disease mechanisms we immunophenotyped a patient with CRB1 related retinal dystrophy that was masquerading as intermediate uveitis at different time-points during follow-up and found several pronounced changes in the immune system that we described in chapter 6. We then used immunophenotyping on a larger scale and applied several high-throughput techniques to immunophenotype the blood of patients with one of three subtypes of non-infectious uveitis in order to better understand pathways underlying NIU and find molecular clues to serve as biomarkers for clinically relevant outcomes or potential therapeutic targets. Patients with active disease and a confirmed diagnosis HLA-B27 associated acute anterior uveitis (in this thesis referred to as AU), idiopathic intermediate uveitis (in this thesis referred to as IU), or Birdshot uveitis (in this thesis referred to as BU) were included, each representing a different primary site of inflammation (e.g., anterior uveitis, intermediate uveitis and posterior uveitis). The combined results of the chapters 7-9 support a strong involvement of multiple layers of the immune system, including microRNAs (chapter 7), T cells (chapter 8) and CD1c+ mDCs (chapter 9) in the pathogenesis of adult non-infectious uveitis.