Chronic danger signaling as driver of autoimmunity in granulomatosis with polyangiitis (GPA)

Break of tolerance is the fundamental step in development of autoimmune diseases. Dysregulation of cell death accompanied by excessive release of danger associated molecular patterns (DAMP) contributes to the break of tolerance. DAMP act as endogenous adjuvants perpetuating self-reactivity, chronic, non-resolving inflammation and subsequent tissue damage. In GPA, which is characterized by chronic granulomatous inflammation and systemic autoimmune vasculitis, we showed inflammation- and pathogen-driven alterations of the adaptive immune response (J Autoimmun. 78:79). Moreover, we demonstrated (i) anomalous expression of the autoantigen proteinase 3 (PR3) and dysregulation of neutrophil cell death that contributes to non-resolving inflammation (Fig. A5-1; J Clin Invest 125: 4107), and (ii) cell death-related release of two prototypic DAMP (HMGB1, IL-33) that contributed to receptor-mediated pro-inflammatory responses within the inflamed tissue in GPA. A causal link between persistent danger signaling and loss of tolerance against Proteinase 3 (PR3) in GPA has to be proven yet.
In blood samples of GPA patients, molecular patterns of danger signals will be analyzed by immunoblotting and multiplex arrays. These will be correlated with disease parameters and compared between diseased subjects and healthy controls. Complex statistical analyses will be performed together with A9. Binding affinities of different isoforms and posttranslational modifications of high mobility group box protein 1 (HMGB1) to PR3 will be determined using microscale thermophoresis. The adjuvant function of HMGB1 will be evaluated using cell lines engineered to express human PR3.