Modulating Metabolic Programming of Memory B cell Activation to Restore B-cell Homeostasis in Autoimmune Disease

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In many cell types outside triggers interact with specific proteins on the cells known as receptors to drive the cells to develop and adopt different ways to meet the cellular needs for development. A type of white blood cell known as B cell or B lymphocyte is critical to our immune system. B cell expresses a protein on its surface known as B cell receptor. B cell receptors specifically recognise foreign proteins to promote our immune defense against bacteria and viruses and also in response to vaccination. B cells that have not yet come in contact with a foreign protein are known as naïve B cells and those that had prior exposure are known as memory B cells, which develop into plasma cells that make proteins known as antibodies to target the foreign proteins expressed on bacteria and viruses. However, we do not know how some memory B cells, compared to naïve B cells, are able to respond rapidly to external triggers. A greater proportion of memory B cells are noted in 'Autoimmune Disease' as Rheumatoid Arthritis and Systemic Lupus Erythematosus, also known as Lupus or SLE, particularly during periods of active disease. A better understanding of how B cells use the B cell receptor signal to adapt for successful development may help us to develop treatment to switch off B cell activation without compromising the ability to switch on at times of need, for example, to fight infections.To this end, it is important to understand how B cells turn the activation signal via the B cell receptor toward successful development into memory B cells and plasma cells. We know that during a state of activation B cells employ specific enzymes to meet the demands on energy and also to generate building blocks for cell development, referred to hereafter as metabolism. In contrast, B cells that are not activated maintain a different program of metabolism. As yet we do not understand the disparity in activation of naïve B cells and memory B cells despite both expressing B cell receptors. Therefore, the proposal seeks to test the hypothesis that the B cell receptors may recruit other proteins to orchestrate different outcomes in response to external triggers.My preliminary work developed in collaboration with Prof Akbar's group based at University College London suggests that, compared to naïve B cells, memory B cells are more efficient at turning B cell receptor signal into successful metabolic program for cell development. Further, memory B cells express cell surface proteins that co-operate with the B cell receptor. We are able to show these effects in B cells isolated from freshly drawn blood samples from healthy people and also from a small number of people with Lupus. Prof Akbar's group has recently reported that proteins known as sestrins regulate metabolic programming in a closely related type of white blood cell or lymphocyte known as T cell, consequently, the function of a specific type of T cell. However, as yet we do not know the role of sestrins in B cells. My preliminary data in collaboration with Prof Akbar's group showed that, in blood samples from healthy people, memory B cells that express higher level of proteins similar to antibody secreting plasma cells also had higher activity of enzymes with the potential to serve the cellular demands for energy and building blocks for cell development. Sestrins were also expressed in memory B cells, but not in naïve B cells. We know that sestrins are expressed in response to stress. Therefore, the discrepancy in sestrin expression between naïve and memory B cells is likely related to the metabolic stress or program that memory B cells employ upon activation. We would now like to perform experiments in samples from people with Lupus to understand whether disturbing this pathway may help our efforts to better target B cells to better control the alterations in B-cell profile to improve outcomes for people with autoimmune disease such as Lupus.