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Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):E898-904. doi: 10.1073/pnas.1118155109. Epub 2012 Mar 19.

Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses.

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  • 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

Genome-wide studies have identified associations between polymorphisms in the IFN regulatory factor-5 (Irf5) gene and a variety of human autoimmune diseases. Its functional role in disease pathogenesis, however, remains unclear, as studies in Irf5(-/-) mice have reached disparate conclusions regarding the importance of this transcription factor in type I IFN production and antibody responses. We identified a spontaneous genomic duplication and frameshift mutation in the guanine exchange factor dedicator of cytokinesis 2 (Dock2) that has arisen in at least a subset of circulating Irf5(-/-) mice and inadvertently been bred to homozygosity. Retroviral expression of DOCK2, but not IRF-5, rescued defects in plasmacytoid dendritic cell and B-cell development, and Irf5(-/-) mice lacking the mutation in Dock2 exhibited normal plasmacytoid dendritic cell and B-cell development, largely intact type I IFN responses, and relatively normal antibody responses to viral infection. Thus, confirmation of the normal Dock2 genotype in circulating Irf5(-/-) mice is warranted, and our data may partly explain conflicting results in this field.

PMID:
22431588
[PubMed - indexed for MEDLINE]
PMCID:
PMC3326475
Free PMC Article

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