MicroRNAs Prevent the Generation of Autoreactive Antibodies

MicroRNAs have been shown to be critical for a number of aspects of immune system regulation and function. Here, we have examined the role of microRNAs in terminal B cell differentiation by analyzing Cd19-Cre ki/+ Dicer1 fl/fl mice. We found that in the absence of Dicer, the transitional and margina...

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Published inImmunity (Cambridge, Mass.) Vol. 33; no. 5; pp. 713 - 722
Main Authors Belver, Laura, de Yébenes, Virginia G., Ramiro, Almudena R.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 24.11.2010
Elsevier Limited
Subjects
Agammaglobulinaemia Tyrosine Kinase
Animals
Antigens, CD19 - genetics
Autoantibodies - biosynthesis
B-Lymphocytes - immunology
Bone marrow
Cell Differentiation
DEAD-box RNA Helicases - genetics
Down-Regulation
Endoribonucleases - genetics
Female
Gene expression
Immune system
Immune Tolerance
Lymphocyte Activation
Medical research
Mice
Mice, Knockout
MicroRNAs
MicroRNAs - metabolism
Protein-Tyrosine Kinases - metabolism
Receptors, Antigen, B-Cell - metabolism
Ribonuclease III
Rodents
Software
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Summary:MicroRNAs have been shown to be critical for a number of aspects of immune system regulation and function. Here, we have examined the role of microRNAs in terminal B cell differentiation by analyzing Cd19-Cre ki/+ Dicer1 fl/fl mice. We found that in the absence of Dicer, the transitional and marginal zone (MZ) B cell compartments were overrepresented and follicular (FO) B cell generation was impaired. microRNA analysis revealed that miR185, a microRNA overexpressed in FO cells, dampened B cell receptor (BCR) signaling through Bruton tyrosine kinase downregulation. Dicer-deficient B cells had a skewed BCR repertoire with hallmarks of autoreactivity, which correlated with high titers of autoreactive antibodies in serum and autoimmune features in females. Together, our results reveal a crucial role for microRNAs in late B cell differentiation and in the establishment of B cell tolerance. ► microRNA ablation impairs follicular but not marginal zone B cell development ► miR185 shifts BCR signaling through Btk modulation ► Dicer-deficient B cells have a skewed BCR repertoire with hallmarks of autoreactivity ► Dicer-deficient female mice accumulate autoantibodies and develop autoimmunity
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ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2010.11.010