The role of Rab46 in immune-mediated inflammatory diseases

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Inflammation is an essential defense mechanism by which the body tries to protect us from infection and injury. However, inappropriate inflammation, where the immune system is active long after the injury has gone, plays a role in many chronic diseases, including rheumatoid arthritis, psoriasis and atherosclerosis. People, who are susceptible to chronic inflammation often, have more than one disease, which suggests there may be a common mechanism that triggers immune cells to act inappropriately. Many immune cells contain special storage packages called granules, which rapidly release their contents upon stimulation (e.g. injury), in order to generate repair. Release of these contents is highly regulated but aberrant release is associated with many inflammatory-based diseases. Rab46 is a new protein that we know plays important roles in the release of granular contents in cells that, like mast cells, respond rapidly to injury. In addition, variations in the Rab46 gene have been associated with diseases characterized by inflammatory conditions. Therefore, in this study, we aim to investigate the contribution of Rab46 to the release of contents from immune cells and determine if impairment of this protein is common in chronic inflammation. We will investigate Rab46 using three distinct approaches: First, there is a resource of genetic and health data from over 500,000 patients stored in the UK Biobank. Genetic analysis of thousands of patients, for example with rheumatoid arthritis, will inform us if variations in the Rab46 gene is common to inflammatory disease. Second, we have a special cohort of patients whose mast cells (a specific set of immune cells involved in allergies) are hypersensitive to stimulation and release their contents too readily (Mast Cell Activation Syndrome: MCAS). In approximately 50% of patients with MCAS, the underlying cause is unknown. We know Rab46 is expressed in these cells; thereby we will sequence the genetic material of MCAS patients and compare genetic variations in the Rab46 gene with control groups. Thirdly, we will determine how Rab46 regulates granule mobility in mast cells by using microscopy to compare granule dynamics in mast cells extracted from wild-type mice to those extracted from mice where the Rab46 gene has been deleted. These studies will provide us with data to determine if Rab46 is an appropriate target for the development of novel therapeutics and/or could be utilized as a diagnostic tool to measure the probability of acquiring chronic inflammatory diseases.