Debanjana Chatterjee1, Carolina Moore2, Baoshan Gao3, Kevin J Clerkin4, Sarah B See1, David Shaked1, Kortney Rogers1, Sarah Nunez1, Yokarla Veras1, Linda Addonizio5, Michael M Givertz6, Yoshifumi Naka5, Donna Mancini4, Rodica Vasilescu7, Charles Marboe7, Susan Restaino4, Joren C Madsen2, Emmanuel Zorn8. 1. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA. 2. Massachusetts General Hospital Transplant Center, Center for Transplantation Science and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 3. Massachusetts General Hospital Transplant Center, Center for Transplantation Science and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Transplant Center, The First Hospital of Jilin University, Changchun, China. 4. Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York, USA. 5. Division of Cardiothoracic Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA. 6. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7. Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, USA. 8. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA; Massachusetts General Hospital Transplant Center, Center for Transplantation Science and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: ez2184@cumc.columbia.edu.
Abstract
BACKGROUND: Cardiac allograft vasculopathy (CAV) has been associated with graft-infiltrating B cells, although their characteristics are still unclear. In this study we examined the frequency, localization and reactivity profile of graft-infiltrating B cells to determine their contribution to the pathophysiology of CAV. METHODS: B cells, plasma cells and macrophages were examined by immunohistochemistry in 56 allografts with CAV, 49 native failed hearts and 25 autopsy specimens. A total of 102 B-cell clones were immortalized directly from the infiltrates of 3 fresh cardiac samples with CAV. Their secreted antibodies were assessed using enzyme-linked immunoassay and flow cytometry. RESULTS: B-cell infiltration was observed around coronary arteries in 93% of allograft explants with CAV. Comparatively, intragraft B cells were less frequent and less dense in the intraventricular myocardium from where routine biopsies are obtained. Plasma cells and macrophages were also detected in 85% and 95% of explants, respectively. Remarkably, B-cell infiltrates were not associated with circulating donor-specific antibodies (DSA) or prior episodes of antibody-mediated rejection (AMR). Among all B-cell clones generated from 3 explants with CAV, a majority secreted natural antibodies reactive to multiple autoantigens and apoptotic cells, a characteristic of innate B cells. CONCLUSIONS: Our study reveals a high frequency of infiltrating B cells around the coronary arteries of allografts with CAV, independent of DSA or AMR. These cells are enriched for innate B cells with a polyreactive profile. The findings shift the focus from conventional DSA-producing B cells to the potentially pathogenic polyreactive B cells in the development of clinical CAV.
BACKGROUND:Cardiac allograft vasculopathy (CAV) has been associated with graft-infiltrating B cells, although their characteristics are still unclear. In this study we examined the frequency, localization and reactivity profile of graft-infiltrating B cells to determine their contribution to the pathophysiology of CAV. METHODS: B cells, plasma cells and macrophages were examined by immunohistochemistry in 56 allografts with CAV, 49 native failed hearts and 25 autopsy specimens. A total of 102 B-cell clones were immortalized directly from the infiltrates of 3 fresh cardiac samples with CAV. Their secreted antibodies were assessed using enzyme-linked immunoassay and flow cytometry. RESULTS: B-cell infiltration was observed around coronary arteries in 93% of allograft explants with CAV. Comparatively, intragraft B cells were less frequent and less dense in the intraventricular myocardium from where routine biopsies are obtained. Plasma cells and macrophages were also detected in 85% and 95% of explants, respectively. Remarkably, B-cell infiltrates were not associated with circulating donor-specific antibodies (DSA) or prior episodes of antibody-mediated rejection (AMR). Among all B-cell clones generated from 3 explants with CAV, a majority secreted natural antibodies reactive to multiple autoantigens and apoptotic cells, a characteristic of innate B cells. CONCLUSIONS: Our study reveals a high frequency of infiltrating B cells around the coronary arteries of allografts with CAV, independent of DSA or AMR. These cells are enriched for innate B cells with a polyreactive profile. The findings shift the focus from conventional DSA-producing B cells to the potentially pathogenic polyreactive B cells in the development of clinical CAV.
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