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Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2014 Feb 01; Vol. 192 (3), pp. 875-85. Date of Electronic Publication: 2013 Dec 30. - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
Antibodies, Antinuclear genetics
Antibodies, Antinuclear immunology
Antigen-Antibody Complex analysis
Disease Models, Animal
Gene Deletion
Humans
Immunoglobulin G genetics
Immunoglobulin G immunology
Intracellular Signaling Peptides and Proteins physiology
Lupus Erythematosus, Systemic
Lupus Nephritis pathology
Lymphocyte Count
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88 deficiency
Myeloid Differentiation Factor 88 genetics
Receptors, Antigen, T-Cell, gamma-delta deficiency
Self Tolerance immunology
Signal Transduction immunology
Signaling Lymphocytic Activation Molecule Associated Protein
Specific Pathogen-Free Organisms
Toll-Like Receptors immunology
Antibodies, Antinuclear biosynthesis
B-Lymphocytes immunology
Dendritic Cells immunology
Germinal Center immunology
Immunoglobulin G biosynthesis
Lupus Nephritis immunology
Myeloid Differentiation Factor 88 physiology
src-Family Kinases deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 192
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 24379120
- Full Text :
- https://doi.org/10.4049/jimmunol.1300683