Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation
A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of death after lung transplantation (LTx), is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early after lung transplantation to form 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 (C3 R102G) that increases complement activation through impaired C3 convertase inactivation in 2 independent LTx recipient cohorts. C3 R102G, identified in at least 1 of 3 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 LTx model, impaired recipient complement regulation led to B cell-dependent CLAD pathology despite moderate differences in graft-infiltrating effector T cells. Dysfunctional complement regulation promoted intragraft accumulation of memory B cells and Ab-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.
Authors
- Victoria R. Davis
- John P. Atkinson (ORCID: https://orcid.org/0000-0002-2514-3441)
- Anusa Thapa (ORCID: https://orcid.org/0000-0001-9486-8350)
- Hrishikesh S. Kulkarni (ORCID: https://orcid.org/0000-0003-4830-5084)
- Daniel R. Calabrese (ORCID: https://orcid.org/0000-0002-0596-3434)
- Howard J. Huang (ORCID: https://orcid.org/0000-0002-3358-6795)
- John R. Greenland (ORCID: https://orcid.org/0000-0003-1422-8367)
- Cory T. Bernadt (ORCID: https://orcid.org/0000-0003-1540-9880)
- Lorena Garnica
- Laneshia K. Tague (ORCID: https://orcid.org/0000-0002-6243-1901)
- Daniel Kreisel (ORCID: https://orcid.org/0000-0002-7711-8651)
- Fuyi Liao (ORCID: https://orcid.org/0000-0001-7733-084X)
- Devesha H. Kulkarni (ORCID: https://orcid.org/0000-0002-8562-8205)
- Derek E. Byers (ORCID: https://orcid.org/0000-0001-7371-9153)
- Ramsey R. Hachem (ORCID: https://orcid.org/0000-0002-0708-1937)
- Catherine Chen (ORCID: https://orcid.org/0000-0001-6108-2044)
- Andrew E. Gelman (ORCID: https://orcid.org/0000-0002-0711-6343)
- Tao Yan (ORCID: https://orcid.org/0000-0002-9162-8551)
- Chad A. Witt (ORCID: https://orcid.org/0000-0002-2267-6920)
- Zhiyi Liu (ORCID: https://orcid.org/0000-0002-8122-8474)
- Xiaobo Wu (ORCID: https://orcid.org/0000-0002-6703-2272)
- Nishanth R Shankar
- Dequan Zhou (ORCID: https://orcid.org/0009-0009-7288-9981)
Institutions
- San Francisco VA Medical Center (US)
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- University of Utah (US)
- Spencer Foundation (US)
- Methodist Hospital (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1172/jci188891
- Citations
- 1
- Primary Topic
- Complement system in diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.80