P07 (2026 - 2030) Identification and comparative analysis of circulating and mucosal autoantibody producing B cells in GPA

Peter Lamprecht (UzL), Antje Müller (UzL)

Project Summary 

Antibodies recognizing neutrophil- and monocyte-derived proteinase 3 (PR3-ANCA) are a diagnostic and pathophysiological hallmark of granulomatosis with polyangiitis (GPA), an ANCA-associated vasculitis entity. Despite successful B cell-depleting therapy, circulating PR3-reactive B cells will re-emerge in GPA and enrichment of autoreactive early plasmablasts in peripheral blood is linked to relapse. Therefore, it is assumed that during quiescent disease or therapeutic efforts, PR3-reactive B cells hide in niches, i.e. inflamed tissues and upon relapse triggered for instance by infectious agents PR3-ANCA produced by tissue-resident plasma cells as well as by other B cell subsets re-appear in the circulation. However, not much is known about clonal relationships between circulating and inflamed tissue-resident autoreactive plasmablasts and plasma cells in ANCA vasculitis. This project will test the hypothesis that circulating PR3-ANCA-producing B and plasma cells are clonally derived from inflamed tissue-resident B and plasma cell repositories, thereby perpetuating humoral autoimmunity and propagating disease pathology. It aims at characterizing circulating and tissue-resident B and plasma cells potentially producing PR3-ANCA by means of sequencing the B cell receptor (BCR) repertoire at the level of individual B cells. As a perspective, identification of PR3-ANCA Ig-producing B cells might be used for early detection of disease progression and relapse and targeted selective depletion of autoreactive pathology-propagating B cells.