The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy

Manon M H Huibers; Alison J Gareau; Aryan Vink; Rianne Kruit; Hannah Feringa; Johanna M T Beerthuijzen; Erica Siera-de Koning; Ton Peeters; Nicolaas de Jonge; Roel A de Weger; Timothy D G Lee

doi:10.1016/j.healun.2014.11.022

The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy

J Heart Lung Transplant. 2015 May;34(5):734-45. doi: 10.1016/j.healun.2014.11.022. Epub 2014 Dec 8.

Affiliations

¹ Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: m.m.h.huibers@umcutrecht.nl.
² Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
³ Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Department of Cardiology, University Medical Center Utrecht, Utretcht, The Netherlands.
⁵ Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.

PMID: 25655346
DOI: 10.1016/j.healun.2014.11.022

Abstract

Background: Cardiac allograft vasculopathy (CAV) is a multifactorial pathology limiting the survival of cardiac transplants. The etiology of CAV is unclear, but antibody-mediated and cellular-mediated responses have been implicated. We, and others, have observed ectopic lymphoid structures (ELS) surrounding epicardial coronary arteries with CAV. The potential contribution of these ELS to CAV has not been elucidated.

Methods: Epicardial coronary arteries were collected from 59 transplant patients at 2 centers and studied for ELS presence and composition using immunohistochemistry. The intima and ELS were isolated, and the expression of the genes involved in tertiary lymphoid organ (TLO) formation was measured by quantitative polymerase chain reaction.

Results: ELS presence was related to survival after transplantation (p = 0.013) and histologic composition of CAV (p < 0.001). ELS contain B and T lymphocytes, macrophages, and antibody-producing (immunoglobulin [Ig] M and/or IgG) plasma cells. A sub-population of B lymphocytes appeared to be cluster of differentiation (CD)20(+)CD27(+) memory B lymphocytes. The messenger RNA expression of TLO markers (lymphotoxin-β, and chemokine [C-C motif] ligand 19 and 21) was significantly higher in ELS than in the neointimal lesions. The ELS observed in this study exhibited some TLO markers but did not exhibit the distinct areas rich in B and T lymphocytes that are normally found in classic TLOs.

Conclusions: The cellular composition of the ELS differs from the cellular infiltrate in CAV intimal lesions. The presence of memory B lymphocytes and plasma producing IgM and IgG cells suggests that ELS are related to local antibody production, potentially contributing to antibody-mediated CAV. ELS associated with coronary vessels containing CAV show features of underdeveloped TLOs; classic TLOs may not develop due to patient immunosuppression.

Keywords: B lymphocytes; allograft vasculopathy; cardiac transplantation; lymphoid neogenesis.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Allografts
Coronary Vessels / immunology*
Coronary Vessels / pathology
Endothelium, Vascular
Female
Graft Rejection / immunology*
Graft Rejection / pathology
Heart Transplantation*
Humans
Immunity, Cellular*
Immunohistochemistry
Lymphoid Tissue / immunology*
Male
Middle Aged
T-Lymphocytes / immunology*
Young Adult