open access publication

Article, 2023

Assessing the role of phosphorylated S6 ribosomal protein in the pathological diagnosis of pulmonary antibody-mediated rejection

The Journal of Heart and Lung Transplantation, ISSN 1053-2498, 1557-3117, Volume 43, 3, Pages 403-413, 10.1016/j.healun.2023.10.002

Contributors

Lunardi, Francesca 0000-0001-5792-4683 [1] Vedovelli, Luca 0000-0003-4847-2333 [1] Pezzuto, Federica 0000-0002-8023-3108 [1] Le Pavec, Jérôme 0000-0003-4426-9645 [2] [3] [4] Dorfmüller, Peter 0000-0003-2499-6829 [4] Ivanovic, Marina 0000-0002-0734-0505 [5] Pena, Tahuanty A 0000-0001-6114-6861 [6] Wassilew, Katharina 0000-0002-8683-465X [7] Perch, Michael 0000-0001-9740-1246 [7] [8] Hirschi, Sandrine [9] Chenard, Marie-Pierre R [9] Sosa, Rebecca A 0000-0002-9860-6830 [10] Goddard, Martin J [11] Neil, Desley A H 0000-0001-9800-6811 [12] Montero-Fernandez, Angeles 0000-0002-2381-6833 [13] Rice, Alexandra J 0000-0002-0527-7960 [14] Cozzi, Emanuele 0000-0001-7855-5055 [1] Rea, Federico 0000-0001-7988-5101 [1] Levine, Deborah Jo 0000-0002-2021-2233 [15] Roux, Antoine [16] [17] Fishbein, Gregory A 0000-0002-3632-5654 [10] Calabrese, Fiorella 0000-0001-5351-9226 (Corresponding author) [1]

Affiliations

  1. [1] University of Padua
    2. [NORA names: Italy; Europe, EU; OECD];
  2. [2] Bicêtre Hospital
    3. [NORA names: France; Europe, EU; OECD];
  3. [3] Service de Pneumologie et de Transplantation Pulmonaire, Groupe Hospitalier Marie-Lannelongue-Paris Saint Joseph, Le Plessis-Robinson, France; Faculty of Medicine, Université Paris-Saclay, Le Kremlin Bicêtre, France; UMR_S 999, Université Paris-Sud, INSERM, Groupe hospitalier Marie-Lannelongue-Saint Joseph, Le Plessis-Robinson, France.
    4. [NORA names: France; Europe, EU; OECD];
  4. [4] Inserm
    5. [NORA names: France; Europe, EU; OECD];
  5. [5] Loyola University Medical Center
    6. [NORA names: United States; America, North; OECD];

Abstract

BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients. METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed. RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%. CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.

Keywords

Antibody-mediated rejection cases, C4d, C4d immunostaining, Pulmonary antibody-mediated rejection, S6 ribosomal protein, accurate pathological diagnosis, agreement, algorithm, antibodies, antibody-mediated rejection, antibody-mediated rejection diagnosis, biopsy, cases, cell components, cells, certainty level, complications, components, control, de novo donor-specific antibodies, diagnosis, diagnostic algorithm, differences, donor-specific antibodies, endothelial expression, endothelium, epithelium, expression, expression values, graft injury, highest sensitivity, highest specificity, immunohistochemistry, immunostaining, inclusion, injury, inter-pathologist agreement, levels, lung, lung transplant patients, lung transplantation, macrophages, mammalian target, mammalian target of rapamycin, mammalian target of rapamycin pathway, multicentre, multicentre retrospective study, objective, pathological diagnosis, pathway, patients, phosphorylated S6 ribosomal protein, phosphorylation, phosphorylation of S6 ribosomal protein, post-lung transplantation complications, protein, protein expression, protein expression values, rapamycin, rejection, rejection cases, rejection diagnosis, retrospective study, ribosomal protein expression, ribosomal proteins, sensitivity, specificity, study, surrogate, target of rapamycin, tissue, transbronchial biopsy, transplant complications, transplant patients, transplantation, values

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