ReviewInsights into the genetic basis and immunopathogenesis of systemic lupus erythematosus from the study of mouse models
Section snippets
Lessons from knock-out and transgenic mice
The fundamental immunologic abnormality in lupus is the loss of tolerance to nuclear antigens. While the nature of the immune abnormalities that lead to this loss of tolerance in human SLE have proved elusive, study of mice with gene deletions or transgenes that promote lupus on non-autoimmune genetic backgrounds has provided a conceptual basis for understanding the immune defects that lead to this breach of tolerance. In general, these can be classified into three broad categories ([11], Table
Insights obtained from study of congenic mice
While study of induced-mutant mice has proved to be an excellent approach for identification of potential immunopathogenic mechanisms in SLE, these mice represent an extreme situation which is rarely duplicated in human SLE, where multiple genes act in concert to produce disease. Indeed, even for gene deleted mice, the presence of lupus susceptibility genes in the C57BL/6 (B6) or 129/Sv backgrounds that were used to generate the mice, has been shown to contribute in some cases to the
Evidence for similarities between mouse and human etiopathogenesis
In recent years, the completion of the human genome project and the availability of high-throughput single nucleotide polymorphism (SNP) genotyping technologies have made it possible to investigate the genetic contributions to disease in a hypothesis-free, comprehensive manner. Although SLE has been a relative late-comer to GWAS, four GWAS have been performed which have led to identification of a number of novel SLE susceptibility genes as well as confirmation of several risk alleles previously
Conclusion
Studies of genetically manipulated mice and congenic mice with chromosomal intervals containing lupus susceptibility genes have elucidated the classes of immune abnormalities that produce lupus and have begun to unravel the mechanisms through which specific genetic polymorphisms promote disease. These experiments provide a context for the understanding and investigation of recently identified human SLE genes, and form a potential basis for the design of novel therapies.
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These authors contributed equally to this work.