Erik Hellbacher: Studies on Lymphoma in Rheumatic Diseases and the Pathophysiology of ANCA-Associated Vasculitis

Abstract

Patients with rheumatic diseases are at increased risk of developing malignant lymphoma, yet the mechanisms linking immune-mediated diseases to lymphomagenesis remain unclear. A deeper understanding of these processes could provide clues to the pathogenesis of both disease categories, improve early risk assessment, and inform preventive strategies. Similarly, the pathophysiological mechanisms of ANCA-associated vasculitis (AAV) and the molecular distinctions underlying the varied clinical outcomes of its subtypes, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), remain poorly understood. Improved insights into these mechanisms could aid in developing more targeted diagnostic tools and treatment strategies.

Paper I investigated B cell-related mechanisms in rheumatoid arthritis (RA)-associated diffuse large B-cell lymphoma (DLBCL). Key findings include elevated levels of several cytokines and chemokines relevant to B-cell biology compared to RA and population controls. In particular, CXCL13 emerged as a protein of interest for its potential role in linking RA to lymphomagenesis.

Paper II examined programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2 in lymphoma tissue from patients with pre-existing rheumatic diseases, with a particular focus on RA-associated DLBCL. A key finding suggests that RA disease severity may influence PD-L1 expression in DLBCL tumor cells.

Paper III characterized lymphomas in patients with pre-existing GPA, focusing on subtypes, localization, and clinical features of both the lymphomas and the underlying rheumatic disease. No clear indications of a predominance of a specific lymphoma subtype were observed, nor was there evidence suggesting local lymphomagenesis in typical GPA target organs.

Paper IV identified key proteins, biological functions, and pathways associated with both shared and distinct disease mechanisms in AAV subtypes, categorized by ANCA serotype into proteinase 3 (PR3)-AAV and myeloperoxidase (MPO)-AAV. The findings highlighted enhanced STAT3 signaling in PR3-AAV and prominent TNF signaling in MPO-AAV, suggesting partially distinct inflammatory processes driving the pathogenesis of these subtypes.

To conclude, the studies in this thesis contribute to the efforts to elucidate the link between autoimmune diseases and lymphoma, as well as the shared and distinct disease mechanisms in AAV.