Granulomatosis with polyangiitis (GPA) is a severe autoimmune disease in which the immune system causes inflammation and damage to small blood vessels, especially in the airways and kidneys. The (auto)immune response in GPA is directed against proteinase-3 (PR3), characterized by the production of antibodies against this protein (PR3-ANCAs). Patients with GPA experience periods of active disease, alternating with remission. The disease flare-ups lead to accumulating and permanent tissue damage. It is therefore crucial to keep patients in prolonged remission. Immunological biomarkers (characteristics of immune cells) to predict the course of GPA are needed, but reliable biomarkers are still lacking. Furthermore, despite recent developments, there are no effective treatment strategies that ensure long-lasting remission.
Different types of immune cells play a role in the disease process of GPA, with B cells having a prominent role. This thesis of Carlo Bonasia focuses on the phenotype (appearance/properties of the cell) and the distribution of immune cells in the blood of GPA patients during active disease, remission, and healthy controls, with a special focus on B cells.
Using advanced techniques such as spectral flow cytometry, we discovered specific patterns in the distribution of immune cells during active disease, particularly certain subpopulations of classical monocytes (a type of white blood cell) that are strongly associated with disease activity. We also found elevated serum concentrations of monocyte-related proteins (chemokines such as CXCL1, CXCL2, and CCL20), which are associated with disease activity. Additionally, we developed a new method to more accurately detect and characterize PR3-specific B cells (the B cells that produce PR3-ANCAs). Furthermore, we found that certain immune-regulating proteins (such as FcγRIIB, CD21, CD86, and BTLA) are differentially expressed on circulating B cells during active GPA, which also showed a strong association with disease activity.
The results of this study have laid a foundation for identifying biomarkers to monitor GPA and provide new therapeutic targets, with the aim of achieving long-term remission.
