Mucosal Breaks of Bacteria Trigger Pathogenic B-cell Responses in ANCA-associated Vasculitis

Description du projet

Le rôle des ruptures de la muqueuse dans la vascularite associée aux ANCA

La vascularite associée aux ANCA (AAV) est une maladie auto-immune qui se caractérise par une inflammation des petits vaisseaux sanguins. Elle implique une combinaison de facteurs génétiques, environnementaux et liés à l’âge. Bien que diverses infections puissent contribuer à son développement, son mécanisme exact demeure encore incompris. Des études suggèrent que des bactéries dans la région des sinus peuvent activer les lymphocytes B par mimétisme moléculaire, et engendrer une AAV. Avec le soutien du programme Actions Marie Skłodowska-Curie, le projet Breaking ANCA se propose d’étudier le rôle des ruptures muqueuses dans la pathogenèse de l’AAV. Les chercheurs séquenceront les lymphocytes B et les microbiomes bactériens et analyseront la réactivité des anticorps monoclonaux. Ces résultats seront validés par l’étude des anticorps sériques dans de larges cohortes de patients souffrant d’AAV. Cela pourrait améliorer notre compréhension des réponses auto-immunes sous-jacentes à la maladie et mettre en lumière le rôle mécanique des bactéries dans le déclenchement de l’AAV.

Objectif

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.