期刊
JOURNAL OF IMMUNOLOGY
卷 201, 期 5, 页码 1442-1451出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1800014
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资金
- National Institutes of Health [R01 HL123340, R01 DK093668, R01 DK103788, R01 AI121244, R01 AI130945, R01 HL125816, R21 AI124129, R21 AI110830, P30 CA016087, MSTP T32GM007308]
- Howard Hughes Medical Institute
- Stony Wold-Herbert Fund
- Colton Center for Autoimmunity, and philanthropy
- Feinberg Lymphoma grant
- Irma T. Hirschl Career Scientist award
- Colton Center for Autoimmunity award
- New York Crohn's Foundation grant
- Beckman Foundation award
- American Gastroenterological Association Clinical Research Pilot award
Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments and contribute to challenges with reproducibility across institutions. Notably, C57BL/6 Hsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2. In this study, we demonstrate the presence of this Dock2 variant in the widely used Nod2(-/-) mice. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic innate immune receptor associated with inflammatory bowel disease susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2(-/-) mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells, and B1a cells in vivo, as well as defects in class switch recombination in vitro. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2(-/-) mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2(-/-) mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2(-/-) mice. Our findings highlight the effects of confounding mutations from widely used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells.
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