1. Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice
- Author
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Hua, Zhaolin, Gross, Andrew J, Lamagna, Chrystelle, Ramos-Hernández, Natalia, Scapini, Patrizia, Ji, Ming, Shao, Haitao, Lowell, Clifford A, Hou, Baidong, and DeFranco, Anthony L
- Subjects
Autoimmune Disease ,Lupus ,Kidney Disease ,Development of treatments and therapeutic interventions ,Aetiology ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Inflammatory and immune system ,Animals ,Antibodies ,Antinuclear ,Antigen-Antibody Complex ,B-Lymphocytes ,Dendritic Cells ,Disease Models ,Animal ,Gene Deletion ,Germinal Center ,Humans ,Immunoglobulin G ,Intracellular Signaling Peptides and Proteins ,Lupus Erythematosus ,Systemic ,Lupus Nephritis ,Lymphocyte Count ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myeloid Differentiation Factor 88 ,Receptors ,Antigen ,T-Cell ,gamma-delta ,Self Tolerance ,Signal Transduction ,Signaling Lymphocytic Activation Molecule Associated Protein ,Specific Pathogen-Free Organisms ,Toll-Like Receptors ,src-Family Kinases ,Immunology - 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.
- Published
- 2014