Project description
The role of mucosal breaks in ANCA-associated vasculitis
ANCA-associated vasculitis (AAV) is an autoimmune disease characterised by inflammation of small blood vessels. It involves a combination of genetic, environmental and age-related factors. While infections may contribute to its development, the exact mechanism remains unclear. Studies suggest that harmful bacteria in the sinus area can activate B-cells through molecular mimicry, leading to AAV. With the support of the Marie Skłodowska-Curie Actions programme, the Breaking ANCA project aims to investigate the role of mucosal breaks in AAV pathogenesis. Researchers will sequence B-cells and bacterial microbiomes and analyse the reactivity of monoclonal antibodies. These findings will be validated by studying serum antibodies in large AAV patient cohorts. Success could enhance our understanding of the autoimmune responses underlying the disease and shed light on the mechanistic role of bacteria in triggering AAV.
Objective
ANCA-associated vasculitis (AAV) is a rare and severe autoimmune disease, characterized by inflammation of the small blood vessels. ANCAs, autoantibodies against proteinase-3 (PR3) or myeloperoxidase (MPO), play a central role in the pathogenesis. They induce excessive activation of neutrophils, resulting in necrotizing injury of small vessels. The loss of tolerance in AAV is thought to be the result of genetic, environmental, and ageing factors. Although infectious triggers are implicated, their exact role in the pathogenesis of AAV remains unclear. Previous studies demonstrated that AAV patients with chronic nasal carriage of Staphylococcus aureus or Corynebacterium tuberculostearicum exhibited a higher relapse rate, and eradication treatment reduced relapses. We hypothesize that pathogenic sinonasal mucosal breaks of bacteria activate autoreactive B-cells through molecular mimicry, resulting in autoimmune responses that mediate AAV. This proposal is to investigate the role of sinonasal mucosal breaks in AAV through repertoire sequencing of peripheral blood and tissue B-cells of AAV patients combined with 16S sequencing of the sinonasal bacterial microbiome. Subsequently, representative monoclonal antibodies will be expressed and reactivity towards ANCAs and sinonasal bacterial antigens investigated. Lastly, the findings will be validated by studying serum antibody reactivity in large cohorts of AAV patients. Success of the proposed studies would transform our understanding of the autoimmune responses in AAV, and potentially elucidate a mechanistic role for sinonasal mucosal breaks of bacteria in triggering disease initiation and progression. Further, success could lead to novel therapeutic approaches focused on preventing mucosal breaks and/or clearance of pathogenic strains. Through this fellowship I hope to develop myself into an independent reseacher, expert of AAV and obtain a position as future academic clinician and principal investigator.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2023-PF-01
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2333 ZA Leiden
Netherlands
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