Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis

Poh Yi Gan, Shaun Andrew Summers, Joshua Ooi, Kim O'Sullivan, Diana Shu Yee Tan, Ruth Cecilia Magdalene Muljadi, Dragana Odobasic, Arthur Richard Kitching, Stephen Roger Holdsworth

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Mast cells contribute to the modulation of the immune response, but their role in autoimmune renal disease is not well understood. Here, we induced autoimmunity resulting in focal necrotizing GN by immunizing wild-type or mast cell-deficient (Kit(W-sh/W-sh)) mice with myeloperoxidase. Mast cell-deficient mice exhibited more antimyeloperoxidase CD4+ T cells, enhanced dermal delayed-type hypersensitivity responses to myeloperoxidase, and more severe focal necrotizing GN. Furthermore, the lymph nodes draining the sites of immunization had fewer Tregs and reduced production of IL-10 in mice lacking mast cells. Reconstituting these mice with mast cells significantly increased the numbers of Tregs in the lymph nodes and attenuated both autoimmunity and severity of disease. After immunization with myeloperoxidase, mast cells migrated from the skin to the lymph nodes to contact Tregs. In an ex vivo assay, mast cells enhanced Treg suppression through IL-10. Reconstitution of mast cell-deficient mice with IL-10-deficient mast cells led to enhanced autoimmunity to myeloperoxidase and greater disease severity compared with reconstitution with IL-10-intact mast cells. Taken together, these studies establish a role for mast cells in mediating peripheral tolerance to myeloperoxidase, protecting them from the development of focal necrotizing GN in ANCA-associated vasculitis.
Original languageEnglish
Pages (from-to)1955 - 1966
Number of pages12
JournalJournal of the American Society of Nephrology
Volume23
Issue number12
DOIs
Publication statusPublished - 2012

Cite this

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title = "Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis",
abstract = "Mast cells contribute to the modulation of the immune response, but their role in autoimmune renal disease is not well understood. Here, we induced autoimmunity resulting in focal necrotizing GN by immunizing wild-type or mast cell-deficient (Kit(W-sh/W-sh)) mice with myeloperoxidase. Mast cell-deficient mice exhibited more antimyeloperoxidase CD4+ T cells, enhanced dermal delayed-type hypersensitivity responses to myeloperoxidase, and more severe focal necrotizing GN. Furthermore, the lymph nodes draining the sites of immunization had fewer Tregs and reduced production of IL-10 in mice lacking mast cells. Reconstituting these mice with mast cells significantly increased the numbers of Tregs in the lymph nodes and attenuated both autoimmunity and severity of disease. After immunization with myeloperoxidase, mast cells migrated from the skin to the lymph nodes to contact Tregs. In an ex vivo assay, mast cells enhanced Treg suppression through IL-10. Reconstitution of mast cell-deficient mice with IL-10-deficient mast cells led to enhanced autoimmunity to myeloperoxidase and greater disease severity compared with reconstitution with IL-10-intact mast cells. Taken together, these studies establish a role for mast cells in mediating peripheral tolerance to myeloperoxidase, protecting them from the development of focal necrotizing GN in ANCA-associated vasculitis.",
author = "Gan, {Poh Yi} and Summers, {Shaun Andrew} and Joshua Ooi and Kim O'Sullivan and Tan, {Diana Shu Yee} and Muljadi, {Ruth Cecilia Magdalene} and Dragana Odobasic and Kitching, {Arthur Richard} and Holdsworth, {Stephen Roger}",
year = "2012",
doi = "10.1681/ASN.2012060572",
language = "English",
volume = "23",
pages = "1955 -- 1966",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "12",

}

Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis. / Gan, Poh Yi; Summers, Shaun Andrew; Ooi, Joshua; O'Sullivan, Kim; Tan, Diana Shu Yee; Muljadi, Ruth Cecilia Magdalene; Odobasic, Dragana; Kitching, Arthur Richard; Holdsworth, Stephen Roger.

In: Journal of the American Society of Nephrology, Vol. 23, No. 12, 2012, p. 1955 - 1966.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis

AU - Gan, Poh Yi

AU - Summers, Shaun Andrew

AU - Ooi, Joshua

AU - O'Sullivan, Kim

AU - Tan, Diana Shu Yee

AU - Muljadi, Ruth Cecilia Magdalene

AU - Odobasic, Dragana

AU - Kitching, Arthur Richard

AU - Holdsworth, Stephen Roger

PY - 2012

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N2 - Mast cells contribute to the modulation of the immune response, but their role in autoimmune renal disease is not well understood. Here, we induced autoimmunity resulting in focal necrotizing GN by immunizing wild-type or mast cell-deficient (Kit(W-sh/W-sh)) mice with myeloperoxidase. Mast cell-deficient mice exhibited more antimyeloperoxidase CD4+ T cells, enhanced dermal delayed-type hypersensitivity responses to myeloperoxidase, and more severe focal necrotizing GN. Furthermore, the lymph nodes draining the sites of immunization had fewer Tregs and reduced production of IL-10 in mice lacking mast cells. Reconstituting these mice with mast cells significantly increased the numbers of Tregs in the lymph nodes and attenuated both autoimmunity and severity of disease. After immunization with myeloperoxidase, mast cells migrated from the skin to the lymph nodes to contact Tregs. In an ex vivo assay, mast cells enhanced Treg suppression through IL-10. Reconstitution of mast cell-deficient mice with IL-10-deficient mast cells led to enhanced autoimmunity to myeloperoxidase and greater disease severity compared with reconstitution with IL-10-intact mast cells. Taken together, these studies establish a role for mast cells in mediating peripheral tolerance to myeloperoxidase, protecting them from the development of focal necrotizing GN in ANCA-associated vasculitis.

AB - Mast cells contribute to the modulation of the immune response, but their role in autoimmune renal disease is not well understood. Here, we induced autoimmunity resulting in focal necrotizing GN by immunizing wild-type or mast cell-deficient (Kit(W-sh/W-sh)) mice with myeloperoxidase. Mast cell-deficient mice exhibited more antimyeloperoxidase CD4+ T cells, enhanced dermal delayed-type hypersensitivity responses to myeloperoxidase, and more severe focal necrotizing GN. Furthermore, the lymph nodes draining the sites of immunization had fewer Tregs and reduced production of IL-10 in mice lacking mast cells. Reconstituting these mice with mast cells significantly increased the numbers of Tregs in the lymph nodes and attenuated both autoimmunity and severity of disease. After immunization with myeloperoxidase, mast cells migrated from the skin to the lymph nodes to contact Tregs. In an ex vivo assay, mast cells enhanced Treg suppression through IL-10. Reconstitution of mast cell-deficient mice with IL-10-deficient mast cells led to enhanced autoimmunity to myeloperoxidase and greater disease severity compared with reconstitution with IL-10-intact mast cells. Taken together, these studies establish a role for mast cells in mediating peripheral tolerance to myeloperoxidase, protecting them from the development of focal necrotizing GN in ANCA-associated vasculitis.

UR - http://www.ncbi.nlm.nih.gov/pubmed/23138486

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