B cell clonal expansion within immune infiltrates in human cardiac allograft vasculopathy

Abstract

Abbreviations: CAV, cardiac allograft vasculopathy; CDR3, complementarity-determining region 3; Ig, immunoglobulin; IGHV, immunoglobulin heavy chain variable region; RCA, right coronary artery; LAD, left anterior descending coronary artery; CIR, circumflex coronary artery; Endo, ventricular endomyocardium; PCR, polymerase chain reaction; PBMC, peripheral blood mononuclear cells.Cardiac allograft vasculopathy (CAV) is associated with intragraft B cell infiltrates.Here, we studied the clonal composition of B cell infiltrates using 4 graft specimens with CAV. Using deep sequencing, we analyzed the immunoglobulin heavy chain variable region repertoire in both graft and blood. Results showed robust B cell clonal expansion in the graft but not in the blood for all cases. Several expanded B cell clones, characterized by their uniquely rearranged complementarity-determining region 3, were detected in different locations in the graft. Sequences from intragraft B cells also showed elevated levels of mutated rearrangements in the graft compared to blood B cells. The number of somatic mutations per rearrangement was also higher in the graft than in the blood, suggesting that B cells continued maturing in situ.Overall, our studies demonstrated B cell clonal expansion in human cardiac allografts with CAV. This local B cell response may contribute to the pathophysiology of CAV through a mechanism that needs to be identified. K E Y W O R D S B cell biology, basic (laboratory) research/science, heart (allograft) function/dysfunction, heart transplantation/cardiology, immunobiology, rejection: chronic S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Moore C, Gao B, Roskin KM, et al. B cell clonal expansion within immune infiltrates in human cardiac allograft vasculopathy. Am J Transplant.

T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy

“…Together, these findings suggest that T cell infiltrates in CAV include a prominent bystander component. In stark contrast, there was a minimal overlap between the peripheral blood and coronary artery B cell repertoires, a finding consistent with our previous studies demonstrating in situ expansion of B cell clones in the context of CAV 13 . The divergence observed between blood and graft B cell populations also argues against the possibility that blood cells could have contaminated the graft tissue.…”

Autoantibodies to LG3 are associated with poor long‐term survival after liver retransplantation

“…Antibodies to non‐HLA antigens, such as autoantibodies or natural polyclonal antibodies, were also described in recipients of solid organs 12 and allogeneic hematopoietic stem cells 13 . Autoantibodies, which may be generated through the exposure of cryptic antigens, are detrimental for the survival of the kidney, 14‐16 lung, 17 heart, 18,19 liver, 20‐22 and intestinal 23 allografts. The prevalence of antibodies to HLA and autoantigens are often higher before retransplantation than before the first transplantation, especially in recipients of kidney grafts 24 .…”

Analysis of T-Cell Receptor Repertoire in Transplantation: Fingerprint of T Cell-mediated Alloresponse

“…NGS technology has made significant progress in the field of TCR analysis ( 92 , 93 ), which introduced high-throughput, and ultra-sensitive techniques to provide detailed information of the TCR arrangement including V, D and J segments and the full sequence of CDR3 ( 94 , 95 ). This high-resolution method is capable of capturing clones at extremely low frequencies.…”