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Publications

Journal Article Preprint Epublish

PubMed: 39605452 DOI: 10.1101/2024.11.17.623951

Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation.

bioRxiv

Authors: Hrishikesh S Kulkarni, Laneshia K Tague, Daniel R Calabrese, Fuyi Liao, Zhiyi Liu, Lorena Garnica, Nishanth Shankar, Xiaobo Wu, Devesha H Kulkarni, Cory Bernardt, Derek Byers, Catherine Chen, Howard J Huang, Chad A Witt, Ramsey R Hachem, Daniel Kreisel, John P Atkinson, John R Greenland, Andrew E Gelman

Affiliations

  • Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Department of Medicine, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, CA, USA.
  • Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Medical Service, Veterans Affairs Health Care System, San Francisco, California, USA.
  • Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
  • Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA.
  • Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Department of Medicine, Houston Methodist Hospital, Houston, TX, USA.
  • Department of Internal Medicine, University of Utah Spencer Fox Eccles School of Medicine, Salt Lake City, UT.

Abstract

A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation, 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 (DSA). In a mouse orthotopic lung transplantation model, impaired recipient complement regulation resulted in more severe obstructive airway lesions when compared to wildtype controls, despite only moderate differences in graft-infiltrating effector T cells. Impaired complement regulation promoted the intragraft accumulation of memory B cells and antibody-secreting cells, resulting in increased DSA levels. In summary, genetic predisposition to complement activation is associated with B cell activation and worse CLAD-free survival.

MeSH

Lung, Complement System Proteins, Lung Transplantation, Allografts, Transplantation