O. (Odilia) Corneth MSc, PhD

Description of Research Line 

Research in my group focuses on the role of B and T lymphocytes in chronic inflammatory diseases of the lung, such as interstitial lung disease (ILD) and sarcoidosis. I am interested in the role of B cell receptor signaling molecules, particularly Bruton’s tyrosine kinase (BTK), and how aberrant signaling can affect B-T cell interaction and the activation status of naïve B cells. Over the past few years, I have studied the role of B cells and BTK in idiopathic pulmonary fibrosis as well as various autoimmune diseases such as Sjögren’s syndrome (SjS), rheumatoid arthritis (RA), ANCA-associated vasculitis and systemic sclerosis, which may be associated with ILD. To study these patients, we have fruitful collaborations with research groups in various university medical centers in the Netherlands. In sarcoidosis, we focus on the T cell compartment, both in patients and in mouse models based on aberrant expression of the negative regulator CTLA4 on the cell surface of Th17 cells and regulatory T cells.

After studying Medicine and Molecular Medicine at Erasmus University Rotterdam, she performed her PhD project at the Rheumatology Department of the Erasmus MC (supervision dr. Erik Lubberts; Prof. Rudi Hendriks, Prof. M. Hazes), studying Th17 cells in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. After obtaining her PhD in 2013, she moved to the Department of Pulmonary Medicine to study B cells, B-T cell interaction, B cell receptor signaling and in particular Bruton’s tyrosine kinase (BTK) in several autoimmune diseases.

1. Corneth OBJ, Neys SFH, Hendriks RW (2022). Aberrant B Cell Signaling in Autoimmune Diseases. Cells. 11(21):3391.
2. Neys SFH, Verstappen GM, Bootsma H, Kroese FGM, Hendriks RW, Corneth OBJ (2022). Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sjögren's Syndrome Patients at Diagnosis. Int J Mol Sci. 23(9):5101.
3. Neys SFH, Heukels P, van Hulst JAC, Rip J, Wijsenbeek MS, Hendriks RW, Corneth OBJ (2021). Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis. Cells. 10(6):1321.
4. Neys SFH, Rip J, Hendriks RW, Corneth OBJ (2021). Bruton's Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease. Drugs. 81(14):1605-1626.
5. Rip J, de Bruijn MJW, Neys SFH, Singh SP, Willar J, van Hulst JAC, Hendriks RW, Corneth OBJ (2021). Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice. Eur J Immunol. 51(9):2251-2265.
6. Von Borstel A, Abdulahad WH, Sanders JS, Rip J, Neys SFH, Hendriks RW, Stegeman CA, Heeringa P, Rutgers A, Corneth OBJ (2019). Evidence for enhanced Bruton's tyrosine kinase activity in transitional and naïve B cells of patients with granulomatosis with polyangiitis. Rheumatology 58(12):2230-2239.
7. Rip J, de Bruijn MJW, Appelman MK, Pal Singh S, Hendriks RW, Corneth OBJ (2019). Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease. Front Immunol. Jan 30; 10:95.
8. Corneth OBJ, Verstappen GMP, Paulissen SMJ, de Bruijn MJW, Rip J, Lukkes M, van Hamburg JP, Lubberts E, Bootsma H, Kroese FGM, Hendriks RW (2017). Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease. Arthritis Rheumatol. 69(6):1313-1324.
9. De Bruijn MJ, Rip J, van der Ploeg EK, van Greuningen LW, Ta VT, Kil LP, Langerak AW, Rimmelzwaan GF, Ellmeier W, Hendriks RW, Corneth OBJ (2017). Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling. J Immunol. 198(8):3058-3068.

Previous studies in the lab have shown that mice overexpressing BTK specifically in B cells spontaneously develop an SLE/SjS-like autoimmune phenotype. We recently found that BTK protein levels in circulating B cells of autoimmune patients are increased, compared to healthy B cells. In active RA and SjS patients, these levels correlate with autoantibodies and in SjS with T cell infiltration in the affected organs. Furthermore, treatment of SjS patients with abatacept (CTLA4-Ig), which targets T cell co-stimulation, reduces BTK expression in their B cells to levels of healthy individuals, indicating that B-T cell interaction affects BTK in B cells and drives autoimmunity. We also studied B cells in IPF, a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. We showed that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve patients with IPF. We observed increased anti-immunoglobulin-induced phosphorylation of BTK in naïve but not in memory B cells of patients with IPF. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with mainly anti-fibrotic activity, induced substantial changes in BCR signalling.

FIGURE 1 | Increased B cell receptor (BCR) signaling in patients with idiopathic pulmonary fibrosis (IPF) and effects of nintedanib

PhD students

Stefan Neys

Lieke de Jong

Jelle Miedema, MD, pulmonologist

Post-doctoral researcher

Thomas Koudstaal, MD, pulmonologist