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

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.