Elsevier

Seminars in Immunology

Volume 21, Issue 6, December 2009, Pages 372-382
Seminars in Immunology

Review
Insights into the genetic basis and immunopathogenesis of systemic lupus erythematosus from the study of mouse models

https://doi.org/10.1016/j.smim.2009.10.005Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by production of autoantibodies directed against nuclear antigens resulting in formation of immune complexes that deposit in multiple organs causing tissue damage. SLE is a complex genetic disease in which variations in multiple genes, each with a modest effect size, contribute to disease genesis. Given this genetic complexity, identification of the role of individual polymorphisms is challenging. In this context, studies of mouse models of lupus have been particularly informative. Here we review the findings arising from the study of gene deleted, transgenic and congenic lupus-prone 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.

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