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Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

Hrishikesh S. Kulkarni,¹ Laneshia K. Tague,² Daniel R. Calabrese,³ Fuyi Liao,⁴ Zhiyi Liu,⁴ Lorena Garnica,² Nishanth R. Shankar,² Xiaobo Wu,² Devesha H. Kulkarni,¹ Aayusha Thapa,¹ Dequan Zhou,⁴ Yan Tao,² Victoria E. Davis,⁴ Cory T. Bernadt,⁵ Derek E. Byers,² Catherine Chen,⁶ Howard J. Huang,⁷ Chad A. Witt,² Ramsey R. Hachem,⁸ Daniel Kreisel,⁴ John P. Atkinson,² John R. Greenland,³ and Andrew E. Gelman⁴

Published November 11, 2025 - More info

A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation (LTx), is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early post-lung transplantation to form the C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3R102G) that increases complement activation through impaired C3 convertase inactivation in two independent LTx recipient cohorts. C3R102G, identified in at least one out of three LTx recipients, was associated with worse CLAD-free survival, particularly in the subset of recipients who developed donor-specific antibodies (DSAs). In a mouse orthotopic lung transplant model, impaired recipient complement regulation led to B cell-dependent CLAD pathology despite moderate differences in graft-infiltrating effector T cells. Dysregulated complement regulation promoted intragraft accumulation of memory B cells and antibody-secreting cells, leading to increased local and circulating DSA levels in mice. In summary, genetic predisposition to complement activation is associated with an increased humoral response and worse CLAD-free survival.

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