title: Antibodies to self-antigens predispose to primary lung allograft dysfunction and chronic rejection.
abstract: BACKGROUND
  Primary graft dysfunction (PGD) is a known risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation. Here, we report that preformed antibodies to self-antigens increase PGD risk and promote BOS.
  
  
  METHODS
  Adult lung transplant recipients (n = 142) were included in the study. Primary graft dysfunction and BOS were diagnosed based on International Society for Heart and Lung Transplantation guidelines. Antibodies to self-antigens k-alpha-1 tubulin, collagen type V, and collagen I were quantitated using standardized enzyme-linked immunosorbent assays, and cytokines were analyzed using Luminex immunoassays (Biosource International, Camirillo, CA). Human leukocyte antigen (HLA) antibodies were measured using Flow-PRA (One Lambda, Canoga Park, CA).
  
  
  RESULTS
  Lung transplant recipients with pretransplant antibodies to self-antigens had increased risk of PGD (odds ratio 3.09, 95% confidence interval: 1.2 to 8.1, p = 0.02) compared with recipients without. Conversely, in patients with PGD, 34.7% were positive for pretransplant antibodies whereas in the PGD negative group, only 14.6% had antibodies (p = 0.03). Antibody positive patients demonstrated high levels of proinflammatory cytokines interleukin (IL)-1β (2.1-fold increase), IL-2 (3.0), IL-12 (2.5), IL-15 (3.0), and chemokines interferon-inducible protein-10 (3.9) and monocyte chemotactic protein-1 (3.1; p < 0.01 for all). On 5-year follow-up, patients without antibodies showed greater freedom from development of HLA antibodies compared with patients who had antibodies (class I: 67% versus 38%, p = 0.001; class II: 71% versus 41%, p < 0.001). Patients with pretransplant antibodies were found to have an independent relative risk of 2.3 (95% confidence interval: 1.7 to 4.5, p = 0.009) for developing BOS.
  
  
  CONCLUSIONS
  Presence of antibodies to self-antigens pretransplant increases the risk of PGD immediately after transplant period and BOS on long-term follow-up. Primary graft dysfunction is associated with an inflammatory cascade that augments the alloimmune (anti-HLA) response that predisposes to BOS.
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Bharat
authors.forename: Deepti
authors.initials: D
authors.lastname: Saini
authors.forename: Nancy
authors.initials: N
authors.lastname: Steward
authors.forename: Ramsey
authors.initials: R
authors.lastname: Hachem
authors.forename: Elbert P
authors.initials: EP
authors.lastname: Trulock
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Meyers
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001989:Bronchiolitis Obliterans / Q000276:immunology*; D002908:Chronic Disease; D024042:Collagen Type I / Q000276:immunology; D024062:Collagen Type V / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D055031:Primary Graft Dysfunction / Q000276:immunology*; D012307:Risk Factors; D014404:Tubulin / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024042:Collagen Type I; D024062:Collagen Type V; D014404:Tubulin