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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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2010-11, Vol.33 (5), p.713-722
Main Authors: Belver, Laura, de Yébenes, Virginia G., Ramiro, Almudena R.
Format: Article
Language:English
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
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2010.11.010