Our understanding of immune recognition and response to infection and non-infectious forms of cell damage and death is rapidly increasing. The major focus is on host immunity and microbiological ...invasion. However, it is also clear that these same pathways are important in the initiation and maintenance of autoimmunity and the damage caused to targeted organs. Understanding the involvement of cell death in autoimmune disease is likely to help define critical pathways in the immunopathogenesis of autoimmune disease and new therapeutic targets. An important immune responder cell population in host defense and autoimmunity is the neutrophil. One autoimmune disease where neutrophils play important roles is MPO-ANCA Microscopic Vasculitis. This a severe disease that results from inflammation to small blood vessels in the kidney, the glomeruli (high blood flow and pressure filters). One of the best studied ways in which neutrophils participate in this disease is by cell death through NETosis resulting in the discharge of proinflammatory enzymes and nuclear fragments. In host defense against infection this process helps neutralize pathogens however in auto immunity NETosis results in injury and death to the surrounding healthy tissues. The major autoimmune target in this disease is myeloperoxidase (MPO) which is found uniquely in the cytoplasm of neutrophils. Although the kidney is the major organ targeted in this disease MPO is not expressed in the kidney. Autoantibodies target surface MPO on activated circulating neutrophils resulting in their lodgment in glomerular capillaries where they NETose releasing extracellularly MPO and nuclear fragments initiating injury and planting the key autoantigen MPO. It is the cell death of neutrophils that changes the kidney from innocent bystander to major autoimmune target. Defining the immunopathogenesis of this autoimmune disease and recognizing critical injurious pathways will allow therapeutic intervention to block these pathways and attenuate autoimmune injury. The insights (regarding mechanisms of injury and potential therapeutic targets) are likely to be highly relevant to many other autoimmune diseases.
Neutrophils are no longer seen as leukocytes with a sole function of being the essential first responders in the removal of pathogens at sites of infection. Being armed with numerous pro- and ...anti-inflammatory mediators, these phagocytes can also contribute to the development of various autoimmune diseases and can positively or negatively regulate the generation of adaptive immune responses. In this review, we will discuss how myeloperoxidase, the most abundant neutrophil granule protein, plays a key role in the various functions of neutrophils in innate and adaptive immunity.
The NLRP3 inflammasome is an intracellular platform that converts the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18 to their active forms in response to ‘danger’ signals, which can be ...either host or pathogen derived, and mediates a form of inflammatory cell death called pyroptosis. This component of the innate immune system was initially discovered because of its role in rare autoinflammatory syndromes called cryopyrinopathies, but it has since been shown to mediate injurious inflammation in a broad range of diseases. Inflammasome activation occurs in both immune cells, primarily macrophages and dendritic cells, and in some intrinsic kidney cells such as the renal tubular epithelium. The NLRP3 inflammasome has been implicated in the pathogenesis of a number of renal conditions, including acute kidney injury, chronic kidney disease, diabetic nephropathy and crystal‐related nephropathy. The inflammasome also plays a role in autoimmune kidney disease, as IL‐1β and IL‐18 influence adaptive immunity through modulation of T helper cell subsets, skewing development in favour of Th17 and Th1 cells that are important in the development of autoimmunity. Both IL‐1 blockade and two recently identified specific NLRP3 inflammasome blockers, MCC950 and β‐hydroxybutyrate, have shown promise in the treatment of inflammasome‐mediated conditions. These targeted therapies have the potential to be of benefit in the growing number of kidney diseases in which the NLRP3 inflammasome has been implicated.
Summary at a Glance
Recent studies in animal models and cell culture suggest a broad role for NLRP3 inflammasome activation in renal disease. Hutton et al provide a timely review of the latest animal and human data in this important area, and discuss therapeutic opportunities afforded by targeting the inflammasome.
IntroductionThis poster will explore the experiences of three junior doctors during their inpatient psychiatry placements. These doctors are Foundation Year 1, Foundation Year 2, and Foundation Year ...3 doctors - i.e. not psychiatry trainees.ObjectivesDue to the nature of the UK Foundation Programme, many FY doctors will not have chosen to work in psychiatry and will have been given the rotation as part of a package of jobs. Studies have shown that the risk of burnout is higher when a doctor working in psychiatry did not identify it as their top career choice (Jovanović, N. et al. (2016) European Psychiatry, 32, pp. 34–41). Lack of supervision is also a risk factor for burnout (Jovanović, N. et al. (2016) European Psychiatry, 32, pp. 34–41).A phenomenological study(Beattie, S. et al. (2017) BMJ Open, 7(9)) demonstrated that job satisfaction and morale amongst junior doctors in psychiatry can be positively influenced by a sense of connectedness, clear role definition, structure and appropriate responsibility. Additionally, junior doctors’ experience of psychiatry, positive or negative, can influence their future career plans (Stott, J., Haywood, J. and Crampton, P. (2021) 43(10), pp. 1196–1202); this has important implications for recruitment into the specialty.MethodsThree junior doctors were interviewed. These consisted of two Foundation Year doctors, and one doctor who has completed FY2 but is working as a locum and not currently in training. They were asked about memorable experiences during their psychiatry placements. Additionally, they were asked about their emotions regarding work at the very start of their placements and towards the end.ResultsThe junior doctors that participated in interviews for the poster initially found the psychiatric inpatient setting challenging and overwhelming. Some of the challenges focused on the occasionally violent and risky nature of the ward and adjusting to that environment. However, all three doctors were pleasantly surprised by the way they adapted to the ward, the supportive nature of the team, and the rewarding experience of seeing very unwell patients get better.ConclusionsOverall the interviews demonstrated that there is a significant emotional impact on junior doctors working in psychiatry, particularly when it is their first experience of in-patient psychiatry. However, this emotional demand can be mitigated by a supportive multi-disciplinary team and good quality supervision.Disclosure of InterestNone Declared
Anti-myeloperoxidase vasculitis (MPO-AAV) is a life-threatening autoimmune disease which causes severe inflammation of small blood vessels, mainly in the kidney. As for many other autoimmune ...diseases, current treatments, which consist of general immunosuppressants, are partially effective, toxic and broadly immunosuppressive, causing significant and serious adverse effects in many patients. Therefore, there is an urgent need for more targeted and less harmful therapies. Tolerogenic dendritic cells, regulatory T cells and stem cells have emerged as attractive, new and safer options for the treatment for various autoimmune diseases due to their unique and selective immunosuppressive capacity. In this review, we will discuss how these cellular therapies offer potential to become novel and safer treatments for MPO-AAV.
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