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Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation
Hrishikesh S Kulkarni1,2, Laneshia K Tague1, Daniel R Calabrese3,4
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Biorxiv : the Preprint Server for Biology
|November 28, 2024
Summary
Genetic predisposition to complement activation is linked to worse outcomes after lung transplantation (LTx). This genetic factor promotes B cell activation, increasing the risk of chronic lung allograft dysfunction (CLAD).
Area of Science:
- Immunology
- Transplantation Science
- Genetics
Background:
- Chronic lung allograft dysfunction (CLAD) is a major cause of mortality following lung transplantation (LTx).
- The complement system plays a crucial role in innate and adaptive immunity, becoming active early after LTx.
- Understanding the genetic factors influencing complement activation is vital for improving LTx outcomes.
Purpose of the Study:
- To investigate the association between a specific genetic polymorphism in complement component 3 (C3R102G) and CLAD-free survival in LTx recipients.
- To explore the role of impaired complement regulation in adaptive alloimmunity and CLAD development.
- To determine the impact of complement activation on B cell populations and donor-specific antibody (DSA) levels.
Main Methods:
- Analysis of a functional C3 polymorphism (C3R102G) in two independent LTx recipient cohorts.
- Assessment of CLAD-free survival in relation to C3R102G status, particularly in DSA-positive recipients.
- Utilizing a mouse orthotopic lung transplantation model to study the effects of impaired complement regulation on graft pathology and immune cell infiltration.
Main Results:
- The C3R102G polymorphism, present in over one-third of LTx recipients, was associated with significantly worse CLAD-free survival.
- This association was more pronounced in recipients who developed donor-specific antibodies (DSA).
- In a mouse model, impaired complement regulation led to more severe airway lesions and increased intragraft accumulation of memory B cells and antibody-secreting cells, correlating with higher DSA levels.
Conclusions:
- A genetic predisposition to enhanced complement activation, via the C3R102G polymorphism, is linked to poorer CLAD-free survival after lung transplantation.
- Impaired complement regulation promotes B cell activation and antibody production, contributing to the development of CLAD.
- Targeting complement pathways may offer a therapeutic strategy to mitigate CLAD and improve long-term lung allograft survival.
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