Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development
Type 1 diabetes (T1D) results from a coordinated autoimmune attack of insulin producing beta cells in the pancreas by the innate and adaptive immune systems, beta cell death being predominantly T cell-mediated. In addition to T cells, peripheral B cells are important in T1D progression. The thymus o...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01281/full |
| _version_ | 1828426577920131072 |
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| author | Ana Isabel Pinto Jennifer Smith Miriam R. Kissack Karen G. Hogg E. Allison Green E. Allison Green |
| author_facet | Ana Isabel Pinto Jennifer Smith Miriam R. Kissack Karen G. Hogg E. Allison Green E. Allison Green |
| author_sort | Ana Isabel Pinto |
| collection | DOAJ |
| description | Type 1 diabetes (T1D) results from a coordinated autoimmune attack of insulin producing beta cells in the pancreas by the innate and adaptive immune systems, beta cell death being predominantly T cell-mediated. In addition to T cells, peripheral B cells are important in T1D progression. The thymus of mice and man also contains B cells, and lately they have been linked to central tolerance of T cells. The role of thymic B cells in T1D is undefined. Here, we show there are abnormalities in the thymic B cell compartment before beta cell destruction and T1D manifestation. Using non-obese diabetic (NOD) mice, we document that preceding T1D development, there is significant accumulation of thymic B cells-partly through in situ development- and the putative formation of ectopic germinal centers. In addition, in NOD mice we quantify thymic plasma cells and observe in situ binding of immunoglobulins to undefined antigens on a proportion of medullary thymic epithelial cells (mTECs). By contrast, no ectopic germinal centers or pronounced intrathymic autoantibodies are detectable in animals not genetically predisposed to developing T1D. Binding of autoantibodies to thymic stroma correlates with apoptosis of mTECs, including insulin-expressing cells. By contrast, apoptosis of mTECs was decreased by 50% in B cell-deficient NOD mice suggesting intrathymic autoantibodies may selectively target certain mTECs for destruction. Furthermore, we observe that these thymic B cell-associated events correlated with an increased prevalence of premature thymic emigration of T cells. Together, our data suggest that the thymus may be a principal autoimmune target in T1D and contributes to disease progression. |
| first_indexed | 2024-12-10T16:48:21Z |
| format | Article |
| id | doaj.art-69966b538b8e4bafbffb3f28f54dd3fe |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T16:48:21Z |
| publishDate | 2018-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-69966b538b8e4bafbffb3f28f54dd3fe2022-12-22T01:40:59ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-06-01910.3389/fimmu.2018.01281355362Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes DevelopmentAna Isabel Pinto0Jennifer Smith1Miriam R. Kissack2Karen G. Hogg3E. Allison Green4E. Allison Green5Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United KingdomCambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United KingdomCentre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United KingdomCentre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United KingdomCentre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United KingdomCambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United KingdomType 1 diabetes (T1D) results from a coordinated autoimmune attack of insulin producing beta cells in the pancreas by the innate and adaptive immune systems, beta cell death being predominantly T cell-mediated. In addition to T cells, peripheral B cells are important in T1D progression. The thymus of mice and man also contains B cells, and lately they have been linked to central tolerance of T cells. The role of thymic B cells in T1D is undefined. Here, we show there are abnormalities in the thymic B cell compartment before beta cell destruction and T1D manifestation. Using non-obese diabetic (NOD) mice, we document that preceding T1D development, there is significant accumulation of thymic B cells-partly through in situ development- and the putative formation of ectopic germinal centers. In addition, in NOD mice we quantify thymic plasma cells and observe in situ binding of immunoglobulins to undefined antigens on a proportion of medullary thymic epithelial cells (mTECs). By contrast, no ectopic germinal centers or pronounced intrathymic autoantibodies are detectable in animals not genetically predisposed to developing T1D. Binding of autoantibodies to thymic stroma correlates with apoptosis of mTECs, including insulin-expressing cells. By contrast, apoptosis of mTECs was decreased by 50% in B cell-deficient NOD mice suggesting intrathymic autoantibodies may selectively target certain mTECs for destruction. Furthermore, we observe that these thymic B cell-associated events correlated with an increased prevalence of premature thymic emigration of T cells. Together, our data suggest that the thymus may be a principal autoimmune target in T1D and contributes to disease progression.https://www.frontiersin.org/article/10.3389/fimmu.2018.01281/fulltype 1 diabetesthymic B cellsautoreactive antibodynon-obese diabeticmedullary thymic epithelial cells |
| spellingShingle | Ana Isabel Pinto Jennifer Smith Miriam R. Kissack Karen G. Hogg E. Allison Green E. Allison Green Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development Frontiers in Immunology type 1 diabetes thymic B cells autoreactive antibody non-obese diabetic medullary thymic epithelial cells |
| title | Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development |
| title_full | Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development |
| title_fullStr | Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development |
| title_full_unstemmed | Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development |
| title_short | Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development |
| title_sort | thymic b cell mediated attack of thymic stroma precedes type 1 diabetes development |
| topic | type 1 diabetes thymic B cells autoreactive antibody non-obese diabetic medullary thymic epithelial cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.01281/full |
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