Investigation of the Role of Antibodies against Adeno-Associated Virus Type 5 and Platelet-Derived Growth Factor Receptor Alpha in Skin Fibrosis and Interstitial Lung Disease in Systemic Sclerosis

• Applicants: Dr. Dennis Bleck; Professor Dr. Armando Gabrielli
• Subject Area: Rheumatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566670393

In fibrotic diseases, pathological deposition of extracellular matrix over the course of the disease leads to loss of function of the affected tissue. This loss of function can lead to organ failure or even death. Fibrotic tissue remodelling has been implicated in up to 45% of deaths in the developed world. A prototypical systemic fibrotic disease is systemic sclerosis (SSc). Stimulatory autoantibodies to platelet-derived growth factor receptor alpha (PDGFRα) are key mediators of fibroblast activation. Viruses have long been suspected as an initial trigger of SSc, but conclusive data have been lacking. We hypothesise that adeno-associated virus 5 (AAV5) binding to PDGFRα triggers an immune response leading to loss of immune tolerance to PDGFRα and formation of agonistic autoantibodies to PDGFRα. Our preliminary data show that AAV5 is present in lung tissue from SSc patients with interstitial lung disease (ILD) and that AAV5 binds to PDGFRα and uses it as an anchor point to enter target cells. Using surface plasmon resonance, the monoclonal agonistic anti-PDGFRα antibody VHPAM-Vκ16F4 was shown to bind to the AAV5 capsid and form high-affinity complexes with PDGFRα and the AAV5 capsid. The formation of complexes of PDGFRα and AAV5 capsid was also demonstrated with anti-PDGFRα antibodies obtained by immunoaffinity purification from SSc patients. In the present application, we plan to quantify and isolate antibodies directed against AAV5 and PDGFRα. The presence of anti-AAV5/PDGFRα antibodies will be correlated with the different manifestations of SSc. In addition, AAV5/PDGFRα reactive B cells will be isolated and their affinity maturation towards PDGFRα will be analysed to provide evidence that the presence of AAV5 can lead to humoral autoimmunity against PDGFRα. In addition, the role of anti-AAV5/PDGFRα antibodies in SSc-associated ILD and skin fibrosis will be investigated using lung organoids and ex vivo skin sections. In addition to histological methods, state-of-the-art spatial OMICS methods will be available for analysis.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Jörg Hans Wilhelm Distler