Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN

Diana Shu Yee Tan, Poh Yi Gan, Kim O'Sullivan, Maree Vanessa Hammett, Shaun Andrew Summers, Joshua Ooi, Brita A Lundgren, Richard Lennox Boyd, Hamish S Scott, Arthur Richard Kitching, Ann Patricia Chidgey, Stephen Roger Holdsworth

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of peripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects of immunizing Mpo(-/-) mice, Aire(-/-) mice, and control littermates with MPO. Immunized Mpo(-/-) and Aire(-/-) mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephritogenic dose of anti-glomerular basement membrane antibody, Aire(-/-) mice had more severe renal disease than Aire(+/+) mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell-mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN.
Original languageEnglish
Pages (from-to)573 - 585
Number of pages13
JournalJournal of the American Society of Nephrology
Volume24
Issue number4
DOIs
Publication statusPublished - 2013

Cite this

Tan, Diana Shu Yee ; Gan, Poh Yi ; O'Sullivan, Kim ; Hammett, Maree Vanessa ; Summers, Shaun Andrew ; Ooi, Joshua ; Lundgren, Brita A ; Boyd, Richard Lennox ; Scott, Hamish S ; Kitching, Arthur Richard ; Chidgey, Ann Patricia ; Holdsworth, Stephen Roger. / Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN. In: Journal of the American Society of Nephrology. 2013 ; Vol. 24, No. 4. pp. 573 - 585.
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title = "Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN",
abstract = "Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of peripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects of immunizing Mpo(-/-) mice, Aire(-/-) mice, and control littermates with MPO. Immunized Mpo(-/-) and Aire(-/-) mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephritogenic dose of anti-glomerular basement membrane antibody, Aire(-/-) mice had more severe renal disease than Aire(+/+) mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell-mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN.",
author = "Tan, {Diana Shu Yee} and Gan, {Poh Yi} and Kim O'Sullivan and Hammett, {Maree Vanessa} and Summers, {Shaun Andrew} and Joshua Ooi and Lundgren, {Brita A} and Boyd, {Richard Lennox} and Scott, {Hamish S} and Kitching, {Arthur Richard} and Chidgey, {Ann Patricia} and Holdsworth, {Stephen Roger}",
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pages = "573 -- 585",
journal = "Journal of the American Society of Nephrology",
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Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN. / Tan, Diana Shu Yee; Gan, Poh Yi; O'Sullivan, Kim; Hammett, Maree Vanessa; Summers, Shaun Andrew; Ooi, Joshua; Lundgren, Brita A; Boyd, Richard Lennox; Scott, Hamish S; Kitching, Arthur Richard; Chidgey, Ann Patricia; Holdsworth, Stephen Roger.

In: Journal of the American Society of Nephrology, Vol. 24, No. 4, 2013, p. 573 - 585.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN

AU - Tan, Diana Shu Yee

AU - Gan, Poh Yi

AU - O'Sullivan, Kim

AU - Hammett, Maree Vanessa

AU - Summers, Shaun Andrew

AU - Ooi, Joshua

AU - Lundgren, Brita A

AU - Boyd, Richard Lennox

AU - Scott, Hamish S

AU - Kitching, Arthur Richard

AU - Chidgey, Ann Patricia

AU - Holdsworth, Stephen Roger

PY - 2013

Y1 - 2013

N2 - Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of peripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects of immunizing Mpo(-/-) mice, Aire(-/-) mice, and control littermates with MPO. Immunized Mpo(-/-) and Aire(-/-) mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephritogenic dose of anti-glomerular basement membrane antibody, Aire(-/-) mice had more severe renal disease than Aire(+/+) mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell-mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN.

AB - Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of peripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects of immunizing Mpo(-/-) mice, Aire(-/-) mice, and control littermates with MPO. Immunized Mpo(-/-) and Aire(-/-) mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephritogenic dose of anti-glomerular basement membrane antibody, Aire(-/-) mice had more severe renal disease than Aire(+/+) mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell-mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN.

UR - http://www.ncbi.nlm.nih.gov/pubmed/23393320

U2 - 10.1681/ASN.2012090898

DO - 10.1681/ASN.2012090898

M3 - Article

VL - 24

SP - 573

EP - 585

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 4

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