Humoral immunity to lung antigens early post-transplant confers risk for chronic lung allograft dysfunction

BACKGROUND: Autoantibodies and de novo donor HLA-specific antibodies (dnDSA) may contribute to chronic lung allograft dysfunction (CLAD). However, the breadth of reactivities against self-antigens and their association with CLAD has been underexamined. In a single-center study, we screened lung transplant (LTx) recipients for novel autoantibodies at transplant and 6 months post-LTx, assessed dnDSA exposure, and CLAD-free survival. METHODS: Serum samples were collected from 89 crossmatch-negative bilateral LTx recipients at the time of LTx and 6 months post-LTx, before a CLAD diagnosis, for autoantibody screening using a custom antigen microarray. RESULTS: Patients who developed CLAD by 5 years post-LTx demonstrated a decrease in average IgG reactivity, but no decrease in IgM reactivity when measured at 6 months post-LTx. IgG anti-tropoelastin, SP-D, and thyroglobulin autoantibodies were significantly elevated 6 months post-LTx in patients who developed CLAD by 5 years, compared to those who remained CLAD-free at 5 years. In contrast, patients who remained CLAD-free at 5 years had elevated levels of IgG anti-CENP-B at both timepoints and PM/SCL100 at 6 months post-LTx, suggesting these may confer protection. Exposure to autoantibodies against lung-enriched targets and dnDSA conferred increased CLAD risk. CONCLUSIONS: We identified novel autoantibodies associated with CLAD-free survival, bolstering the independent relationship between autoantibodies and CLAD. We also identified autoantibody signatures that are associated with a marked increase in CLAD risk. Exposure to lung-enriched targets and dnDSA may have a reciprocal amplifying effect that lies on a tissue-specific mechanistic pathway leading to CLAD. J Heart Lung Transplant 2025;44:1109-1119 (c) 2025 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).