Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-cell–mediated autoimmunity
| Autor: | Bethany Scott, Jonathan Deane, Elizabeth R. Walsh, Prapaporn Pisitkun, Elisaveta Voynova, Silvia Bolland, Rachel R. Caspi |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
CD40 Ligand
Receptors Antigen T-Cell Autoimmunity Mice Transgenic Adaptive Immunity Biology Lymphocyte Activation Real-Time Polymerase Chain Reaction medicine.disease_cause Major histocompatibility complex Mice Immune system medicine Animals Lupus Erythematosus Systemic Signaling Lymphocytic Activation Molecule Associated Protein B cell Autoimmune disease Analysis of Variance B-Lymphocytes Multidisciplinary CD40 Intracellular Signaling Peptides and Proteins virus diseases Germinal center Biological Sciences Flow Cytometry medicine.disease Acquired immune system Immunohistochemistry Immunity Innate Mice Inbred C57BL medicine.anatomical_structure Toll-Like Receptor 7 Immunology biology.protein Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 109:16276-16281 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1209372109 |
| Popis: | Toll-like receptor 7 ( Tlr7 ) has been linked to systemic lupus disease incidence in humans and mice, but how TLR7 potentiates autoimmunity is unclear. We used a Tlr7 transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined that Tlr7 exerts B-cell–intrinsic effects in promoting spontaneous germinal center (GC) and plasmablast B-cell development, and that these B-cell subsets are dependent on T-cell–derived signals through CD40L and SLAM-associated protein (SAP), but not IL-17. Antigen specificity also factored into TLR7-induced disease, as both a restricted T cell receptor (TCR) specificity and MHC haplotype H2 k/k protected Tlr7 tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop in Tlr7 tgIgH −/− mice, suggesting either that spontaneous TLR7 activation does not occur in dendritic cells, or, if it does occur, cannot drive these events in the absence of B-cell aid. These data indicate that autoimmune disease in Tlr7 tg mice is contingent upon B cells receiving stimulation both through innate pathways and T-cell–derived signals and suggest a codependent relationship between B cells and T cells in the development of autoimmunity. |
| Databáze: | OpenAIRE |
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