C3 GENE variation may clarify why some lung transplant recipients develop chronic rejection over time.
C3 Gene Variant and Chronic Rejection Risk
In this study, investigators evaluated whether a functional C3 gene variant is linked to outcomes after lung transplantation. They focused on the C3R102G polymorphism, which enhances complement activation, and followed two independent cohorts of lung transplant recipients for the development of chronic lung allograft dysfunction (CLAD). Approximately one third of recipients carried the C3 gene variant and these patients experienced worse CLAD free survival, particularly when donor specific antibodies to the lung graft emerged.
Complement System and Humoral Alloimmunity
Building on clinical observations, the team used a mouse orthotopic lung transplant model with impaired complement regulation to explore mechanism. Dysregulated activity in the complement system promoted intragraft accumulation of memory B cells and antibody secreting cells, driving higher levels of donor specific antibodies locally and in the circulation. Despite only moderate differences in graft infiltrating effector T cells, these humoral responses were sufficient to trigger chronic lung allograft dysfunction in the experimental model, mirroring the clinical associations seen in transplant recipients.
Implications for Risk Stratification and Future Therapies
Taken together, the findings support a model in which inherited differences in complement regulation shape the risk of antibody mediated rejection after lung transplantation. The authors report that genetic predisposition to complement activation is associated with an increased humoral response and worse CLAD free survival. In the longer term, C3 gene variant testing could help stratify patients by chronic rejection risk and guide closer monitoring, targeted immunosuppression or future complement directed therapies, although prospective validation and clinical trials will be essential before practice changes. For clinicians, the work reinforces the central role of chronic lung allograft dysfunction as the leading cause of mortality after lung transplantation and highlights complement driven humoral alloimmunity as a key therapeutic target.
Reference: Kulkarni HS et al. Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation. Journal of Clinical Investigation. 2025;doi:10.1172/JCI188891.
