title: Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice.
abstract: The intracellular tyrosine kinase Lyn mediates inhibitory receptor function in B cells and myeloid cells, and Lyn(-/-) mice spontaneously develop an autoimmune and inflammatory disease that closely resembles human systemic lupus erythematosus. TLR-signaling pathways have been implicated in the production of anti-nuclear Abs in systemic lupus erythematosus and mouse models of it. We used a conditional allele of Myd88 to determine whether the autoimmunity of Lyn(-/-) mice is dependent on TLR/MyD88 signaling in B cells and/or in dendritic cells (DCs). The production of IgG anti-nuclear Abs, as well as the deposition of these Abs in the glomeruli of the kidneys, leading to glomerulonephritis in Lyn(-/-) mice, were completely abolished by selective deletion of Myd88 in B cells, and autoantibody production and glomerulonephritis were delayed or decreased by deletion of Myd88 in DCs. The reduced autoantibody production in mice lacking MyD88 in B cells or DCs was accompanied by a dramatic decrease in the spontaneous germinal center (GC) response, suggesting that autoantibodies in Lyn(-/-) mice may depend on GC responses. Consistent with this view, IgG anti-nuclear Abs were absent if T cells were deleted (TCRβ(-/-) TCRδ(-/-) mice) or if T cells were unable to contribute to GC responses as the result of mutation of the adaptor molecule SAP. Thus, the autoimmunity of Lyn(-/-) mice was dependent on T cells and on TLR/MyD88 signaling in B cells and in DCs, supporting a model in which DC hyperactivity combines with defects in tolerance in B cells to lead to a T cell-dependent systemic autoimmunity in Lyn(-/-) mice.
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Zhaolin
authors.initials: Z
authors.lastname: Hua
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gross
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Lamagna
authors.forename: Natalia
authors.initials: N
authors.lastname: Ramos-Hernández
authors.forename: Patrizia
authors.initials: P
authors.lastname: Scapini
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.forename: Haitao
authors.initials: H
authors.lastname: Shao
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Baidong
authors.initials: B
authors.lastname: Hou
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeFranco
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency; D017634:Self Tolerance / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013047:Specific Pathogen-Free Organisms; D051193:Toll-Like Receptors / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency*
chemical_list: D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016692:Receptors, Antigen, T-Cell, gamma-delta; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D051193:Toll-Like Receptors; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases