ANCA-associated vasculitides (AAV) are characterized by recurrent, chronic small vessel inflammation and deleterious organ damage. Early disease control by targeted treatment has improved considerably, but the most important clinical challenge now is the recognition and control of flares. This project aims to delineate the immunological basis of disease flares and disease persistence in AAV patients. We have observed that individual AAV patients (in contrast to healthy individuals) can harbour large populations of B cells expressing IgM-ANCA, and that IgM-ANCA can strongly activate complement. Based on this preparatory work, we hypothesize that auto-reactive B cell responses reflect a so far undetermined layer of immunological disease activity in AAV, with IgM B cell responses driving flares. To test this novel hypothesis, the project unites three AAV expert centres that combine unique expertise and technology in autoreactive B cell biology, well-defined cohorts with longitudinal follow-up and biological samples, and patient representatives experienced in supporting translational research. The expected end-product is an immunological definition of (imminent) disease flares in AAV and a novel measure of disease activity. This addresses directly the scope of the call and will be crucial to guide future trials aiming at testing strategies for optimal control of disease.
We hypothesize that phenotypic characteristics of the autoreactive MPO-ANCA B cell response, and in particular the presence and/or activation of IgM MPO-ANCA B cells, reflect immunological processes that drive disease flares.
To test this hypothesis, we formulate the following objectives:
All centres will recruit patients for cellular analyses and select sera from their biobanks/cohorts. PRPs from all centres will receive training via foundation Tools2use. Dr. Maarten de Witt). PRPs will be actively contributing to WP4 as full collaborating partners.
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