Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice

• Published in: The Journal of immunology (1950) Vol. 192; no. 3; pp. 875 - 885
• Main Authors: Hua, Zhaolin, Gross, Andrew J, Lamagna, Chrystelle, Ramos-Hernández, Natalia, Scapini, Patrizia, Ji, Ming, Shao, Haitao, Lowell, Clifford A, Hou, Baidong, DeFranco, Anthony L
• Format: Journal Article
• Language: English
• Published: United States 01.02.2014
• Subjects: Animals; Antibodies, Antinuclear - biosynthesis; Antibodies, Antinuclear - genetics; Antibodies, Antinuclear - immunology; Antigen-Antibody Complex - analysis; B-Lymphocytes - immunology; Dendritic Cells - immunology; Disease Models, Animal; Gene Deletion; Germinal Center - immunology; Humans; Immunoglobulin G - biosynthesis; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Intracellular Signaling Peptides and Proteins - physiology; Lupus Erythematosus, Systemic; Lupus Nephritis - immunology; Lupus Nephritis - pathology; Lymphocyte Count; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - physiology; Receptors, Antigen, T-Cell, gamma-delta - deficiency; Self Tolerance - immunology; Signal Transduction - immunology; Signaling Lymphocytic Activation Molecule Associated Protein; Specific Pathogen-Free Organisms; src-Family Kinases - deficiency; Toll-Like Receptors - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300683

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.