Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 15, Pages E898-E904Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1118155109
Keywords
immune cell development; autoimmunity; viruses
Categories
Funding
- National Institutes of Health [K01DK078318]
- Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases [U54 AI081680, U19 AI083019]
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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.
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