Signs of danger: auto-reactive B cell responses as drivers of disease flares in AAV

Concept

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.

Facts and Figures

Project Lead
MD, PhD H U Scherer
Leiden University
h.u.scherer@lumc.nl
2023–2026
FOREUM research grant: € 599.976

Meet the Team

Project Lead

MD, PhD H U Scherer
Leiden University
h.u.scherer@lumc.nl
Prof. R Toes
Leiden University
MD, PhD Y K O Teng
Leiden University Medical Center
Prof. V Malmström
Karolinska Institutet
Prof. I Gunnarsson
Karolinska Institutet
Prof. A Bruchfeld
Karolinska Institute
Prof. C D. Pusey
Imperial College London
Prof. S P McAdoo
Imperial College London

Objectives

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:

  • To define MPO-ANCA B cells and their characteristics as disease-specific markers that reflect immunological disease activity (IDA) in different phases of MPO-AAV.
  • To evaluate the association between dynamic changes of IgM MPO-ANCA in serum and defined clinical phenotypes, in relation and addition to IgG MPO-ANCA.
  • To generate the molecular tools to unravel potential triggers initiating and maintaining the activation of MPO-ANCA B cells.
  • To evaluate the perception by patients of the novel concept of IDA in AAV versus clinical disease activity based on defined, patient-reported outcomes (PROs).

Goals/Milestones

  • MS1: (Month 6) initiation meeting, technology transfer, PRP training and advise accomplished.
  • MS2: (Month 12) PROs defined and distributed to defined patient groups.
  • MS3: (Month 30) patient/PRO recruitment completed; cellular and serum analyses performed.
  • MS4: (Month 30) BCR repertoire analysis performed; mAb generated and tested.
  • MS5: (Month 36) data integration and analysis completed; manuscripts prepared.

Patient Voice

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.
http://www.tools2use. eu

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