Proprotein Convertase Enzyme Furin as a Biomarker for Immune-Mediated Diseases

The prevalence of immune-mediated diseases is rising rapidly in our aging population. Currently used biomarkers are inaccurate and have a low predictive value, which complicates early diagnosis and evaluation of the efficacy of a given treatment. Consequently, there is an urgent need for novel biomarkers for immune- mediated diseases at present. Proprotein convertase subtilisin/kexin (PCSK) enzymes have an important role in regulating general homeostasis by dictating the bioavailability of a variety of secretory and cell-surface proteins. The first found PCSK enzyme Furin is readily upregulated during immune cell activation. It regulates T cell functions and induces the processing of toll-like receptor 7 in innate immune cells to promote host defense against intracellular and extracellular pathogens. Furthermore, T-cell-expressed Furin favors T helper 1 cell polarization and promotes proper forkhead box P3+ T regulatory cell functions. Hence in addition to its key regulatory role in innate and adaptive immune responses, Furin is crucial for the maintenance of peripheral immunological tolerance. On the contrary, alterations in Furin expression have been associated with several immune-mediated diseases.

This study investigated the role of Furin expression in acute infection, primary Sjögren’s syndrome and rheumatoid arthritis using various detection methods. The main aim was to assess how Furin levels correlate with clinical parameters in order to study its potential value as a biomarker for the aforementioned immune-mediated diseases. The results show that the Furin plasma level does not identify severe infections or initial pathogens in the early phase of infections. However, Furin expression was significantly elevated in both primary Sjögren’s syndrome and rheumatoid arthritis. Elevated Furin levels were associated with high interferon-γ levels and prolonged symptoms of dry eye in the group of patients with primary Sjögren’s syndrome. Patients with high Furin levels also showed a trend toward lower β2-microglobulin levels, erythrocyte sedimentation rate, and systemic disease activity index ESSDAI. In contrast, Furin plasma levels were not associated with clinical parameters in patients with rheumatoid arthritis. However, elevated Furin messenger ribonucleic acid levels were significantly associated with prednisolone use and prednisolone doses, C-reactive protein levels, and general disability index (Health Assessment Questionnaire).

Collectively, this study shows that Furin plasma measurements do not have a predictive or diagnostic value in the early phase evaluation of patients with suspected infection. On the contrary, Furin was significantly upregulated in both primary Sjögren’s syndrome and rheumatoid arthritis, suggesting that it may have a role in the pathogenesis of autoimmune diseases. However, the observations of Furin effects turned out contradictory: Results from the primary Sjögren’s syndrome group suggested its protective role in the disease development, whereas elevated levels in rheumatoid arthritis indicated a more severe and refractory disease. This discrepancy could be a result of its extensive substrate selection. Furin is known to activate both proinflammatory and anti-inflammatory factors, which could lead to its varying effects in terms of distinct pathophysiological mechanisms. Additional studies and novel methods for the detection of Furin are needed to further evaluate the clinical relevance of Furin expression in predicting immune-mediated diseases and understand its fundamental nature in health and disease.