title: Myeloid cells, BAFF, and IFN-gamma establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice.
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.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Scapini
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Hu
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Chu
authors.forename: Thi-Sau
authors.initials: TS
authors.lastname: Migone
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Defranco
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009393:Nephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D011518:Proto-Oncogene Proteins; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D007371:Interferon-gamma; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases