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.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Rd, Clayton, VIC 3168, Australia.
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Summers
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.forename: Kim M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Diana S Y
authors.initials: DS
authors.lastname: Tan
authors.forename: Ruth C M
authors.initials: RC
authors.lastname: Muljadi
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000150:complications*; D002478:Cells, Cultured; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D056747:Immunomodulation; D016753:Interleukin-10 / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D061166:Peripheral Tolerance; D009195:Peroxidase; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10; D009195:Peroxidase