Brief Communication
Donor-Specific Antibodies Are Produced Locally in Ectopic Lymphoid Structures in Cardiac Allografts

https://doi.org/10.1111/ajt.13969Get rights and content
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Cardiac allograft vasculopathy (CAV) is a transplant pathology, limiting graft survival after heart transplantation. CAV arteries are surrounded by ectopic lymphoid structures (ELS) containing B cells and plasma cells. The aim of this study was to characterize the antigenic targets of antibodies produced in ELS. Coronary arteries and surrounding epicardial tissue from 56 transplant recipients were collected during autopsy. Immunofluorescence was used to identify antibody-producing plasma cells. Immunoglobulin levels in tissue lysates were measured by enzyme-linked immunosorbent assay and analyzed for donor-specific HLA antibodies by Luminex assay. Cytokine and receptor expression levels were quantified using quantitative polymerase chain reaction. Plasma cells in ELS were polyclonal and produced IgG and/or IgM antibodies. In epicardial tissue, IgG (p < 0.05) and IgM levels were higher in transplant patients with larger ELS than smaller ELS. In 4 of 21 (19%) patients with ELS, donor-specific HLA type II antibodies were detected locally. Cytokine and receptor expression (CXCR3, interferon γ and TGF-β) was higher in large ELS in the epicardial tissue than in other vessel wall layers, suggesting active recruitment and proliferation of T and B lymphocytes. ELS exhibited active plasma cells producing locally manufactured antibodies that, in some cases, were directed against the donor HLA, potentially mediating rejection with major consequences for the graft.

KEYWORDS

translational research/science
heart transplantation/cardiology
molecular biology
pathology/histopathology
alloantibody
B cell biology
rejection: antibody-mediated (ABMR)
rejection: chronic
vasculopathy

Abbreviations

AID
activation-induced cytidine deaminase
AMR
antibody-mediated rejection
CAV
cardiac allograft vasculopathy
D
donor
DSA
donor-specific antibody
ELISA
enzyme-linked immunosorbent assay
ELS
ectopic lymphoid structures
F
female
FF
fresh frozen
H-CAV
histological cardiac allograft vasculopathy
HTx
heart transplantation
IFN-γ
interferon γ
IHC
immunohistochemistry
ISH
in situ hybridization
ISHLT
International Society of Heart and Lung Transplantation
M
male
neg
negative
pAMR
pathological antibody-mediated rejection
PCR
polymerase chain reaction
P
patient
RQ
relative quantity
TLO
tertiary lymphoid organ
TNF-α
tumor necrosis factor α

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