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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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-beta, 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. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.

Original language	English
Pages (from-to)	734-745
Number of pages	12
Journal	Journal of Heart and Lung Transplantation
Volume	34
Issue number	5
DOIs	https://doi.org/10.1016/j.healun.2014.11.022
Publication status	Published - May 2015

Keywords

cardiac transplantation
allograft vasculopathy
lymphoid neogenesis
B lymphocytes
DONOR-SPECIFIC ANTIBODIES
T-CELLS
B-CELLS
CHRONIC REJECTION
HEART-TRANSPLANTATION
ALLOIMMUNE RESPONSE
MEMORY
NEOGENESIS
TOLERANCE
DISEASE

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10.1016/j.healun.2014.11.022

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Huibers, M. M. H., Gareau, A. J., Vink, A., Kruit, R., Feringa, H., Beerthuijzen, J. M. T., Siera-de Koning, E., Peeters, T., de Jonge, N., de Weger, R. A., & Lee, T. D. G. (2015). The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy. Journal of Heart and Lung Transplantation, 34(5), 734-745. https://doi.org/10.1016/j.healun.2014.11.022

@article{93c25994246c42f8804f59c26b011538,

title = "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-beta, 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. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.",

keywords = "cardiac transplantation, allograft vasculopathy, lymphoid neogenesis, B lymphocytes, DONOR-SPECIFIC ANTIBODIES, T-CELLS, B-CELLS, CHRONIC REJECTION, HEART-TRANSPLANTATION, ALLOIMMUNE RESPONSE, MEMORY, NEOGENESIS, TOLERANCE, DISEASE",

author = "Huibers, {Manon M. H.} and Gareau, {Alison J.} and Aryan Vink and Rianne Kruit and Hannah Feringa and Beerthuijzen, {Johanna M. T.} and {Siera-de Koning}, Erica and Ton Peeters and {de Jonge}, Nicolaas and {de Weger}, {Roel A.} and Lee, {Timothy D. G.}",

year = "2015",

month = may,

doi = "10.1016/j.healun.2014.11.022",

language = "English",

volume = "34",

pages = "734--745",

journal = "Journal of Heart and Lung Transplantation",

issn = "1053-2498",

publisher = "Elsevier USA",

number = "5",

}

Huibers, MMH, Gareau, AJ, Vink, A, Kruit, R, Feringa, H, Beerthuijzen, JMT, Siera-de Koning, E, Peeters, T, de Jonge, N, de Weger, RA & Lee, TDG 2015, 'The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy', Journal of Heart and Lung Transplantation, vol. 34, no. 5, pp. 734-745. https://doi.org/10.1016/j.healun.2014.11.022

TY - JOUR

T1 - The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy

AU - Huibers, Manon M. H.

AU - Gareau, Alison J.

AU - Vink, Aryan

AU - Kruit, Rianne

AU - Feringa, Hannah

AU - Beerthuijzen, Johanna M. T.

AU - Siera-de Koning, Erica

AU - Peeters, Ton

AU - de Jonge, Nicolaas

AU - de Weger, Roel A.

AU - Lee, Timothy D. G.

PY - 2015/5

Y1 - 2015/5

N2 - 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-beta, 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. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.

AB - 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-beta, 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. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.

KW - cardiac transplantation

KW - allograft vasculopathy

KW - lymphoid neogenesis

KW - B lymphocytes

KW - DONOR-SPECIFIC ANTIBODIES

KW - T-CELLS

KW - B-CELLS

KW - CHRONIC REJECTION

KW - HEART-TRANSPLANTATION

KW - ALLOIMMUNE RESPONSE

KW - MEMORY

KW - NEOGENESIS

KW - TOLERANCE

KW - DISEASE

U2 - 10.1016/j.healun.2014.11.022

DO - 10.1016/j.healun.2014.11.022

M3 - Article

C2 - 25655346

SN - 1053-2498

VL - 34

SP - 734

EP - 745

JO - Journal of Heart and Lung Transplantation

JF - Journal of Heart and Lung Transplantation

IS - 5

ER -

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

Abstract

Keywords

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