Abstract
Autoimmunity is traditionally attributed to altered lymphoid cell selection and/or tolerance, whereas the contribution of innate immune cells is less well understood. Autoimmunity is also associated with increased levels of B cell-activating factor of the TNF family (BAFF; also known as B lymphocyte stimulator), a cytokine that promotes survival of self-reactive B cell clones. We describe an important role for myeloid cells in autoimmune disease progression. Using Lyn-deficient mice, we show that overproduction of BAFF by hyperactive myeloid cells contributes to inflammation and autoimmunity in part by acting directly on T cells to induce the release of IFN-gamma. Genetic deletion of IFN-gamma or reduction of BAFF activity, achieved by either reducing myeloid cell hyperproduction or by treating with an anti-BAFF monoclonal antibody, reduced disease development in lyn(-/-) mice. The increased production of IFN-gamma in lyn(-/-) mice feeds back on the myeloid cells to further stimulate BAFF release. Expression of BAFF receptor on T cells was required for their full activation and IFN-gamma release. Overall, our data suggest that the reciprocal production of BAFF and IFN-gamma establishes an inflammatory loop between myeloid cells and T cells that exacerbates autoimmunity in this model. Our findings uncover an important pathological role of BAFF in autoimmune disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Autoantibodies / blood
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Autoantibodies / immunology
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Autoimmunity / genetics
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Autoimmunity / immunology*
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B-Cell Activating Factor / blood
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B-Cell Activating Factor / genetics
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B-Cell Activating Factor / immunology
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B-Cell Activating Factor / metabolism*
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B-Cell Activation Factor Receptor / genetics
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B-Lymphocytes / cytology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Cell Proliferation / drug effects
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Dendritic Cells / cytology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Gene Expression / genetics
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Gene Expression / immunology
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Inflammation / immunology
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Interferon-gamma / blood
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Interferon-gamma / genetics
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Interferon-gamma / metabolism*
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Interferon-gamma / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Macrophages / cytology
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Immunological
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Myeloid Cells / cytology
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Myeloid Cells / drug effects
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Myeloid Cells / immunology*
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Myeloid Cells / metabolism
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Nephritis / genetics
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Nephritis / immunology
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Nephritis / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-hck / genetics
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Spleen / cytology
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Spleen / metabolism
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Spleen / pathology
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Splenomegaly / genetics
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Splenomegaly / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes / transplantation
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src-Family Kinases / genetics*
Substances
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Antibodies, Monoclonal
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Autoantibodies
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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Proto-Oncogene Proteins
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Tnfrsf13c protein, mouse
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Tnfsf13b protein, mouse
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Interferon-gamma
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Hck protein, mouse
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Proto-Oncogene Proteins c-hck
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lyn protein-tyrosine kinase
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proto-oncogene proteins c-fgr
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src-Family Kinases