Spontaneous Autoimmunity in 129 and C57BL/6 Mice—Implications for Autoimmunity Described in Gene-Targeted Mice
Anne E. Bygrave1 , Kirsten L. Rose1 , Josefina Cortes-Hernandez1 , Joanna Warren1 , Robert J. Rigby1 , H. Terence Cook2 , Mark J. Walport1? , Timothy J. Vyse1 , Marina Botto1*
1 Rheumatology Section, Eric Bywaters Centre, Imperial College, London, United Kingdom, 2 Department of Histopathology, Faculty of Medicine, Imperial College, London, United Kingdom
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targeted mice. This suggests an important role in the expression of autoimmunity of as-yet-uncharacterised background genes originating from these parental mouse strains. Using genome-wide linkage analysis, we identified several susceptibility loci, derived from 129 and C57BL/6 mice, mapped in the lupus-prone hybrid (129 ¥ C57BL/6) model. By creating a C57BL/6 congenic strain carrying a 129-derived Chromosome 1 segment, we found that this 129 interval was sufficient to mediate the loss of tolerance to nuclear antigens, which had previously been attributed to a disrupted gene. These results demonstrate important epistatic modifiers of autoimmunity in 129 and C57BL/6 mouse strains, widely used in gene targeting. These background gene influences may account for some, or even all, of the autoimmune traits described in some gene-targeted models of SLE.
Citation: Bygrave AE, Rose KL, Cortes-Hernandez J, Warren J, Rigby RJ, et al. (2004) Spontaneous autoimmunity in 129 and C57BL/6 mice—Implications for autoimmunity described in gene-targeted mice. PLoS Biol 2(8): e243.
Received January 1, 2004; Accepted May 27, 2004; Published August 17, 2004
DOI: 10.1371/journal.pbio.0020243
Copyright: © 2004 Bygrave et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
