Genetic dissection of systemic lupus erythematosus pathogenesis

Partial functional complementation between Sle1 and Sle3/5 demonstrates requirement for intracellular coexpression for full phenotypic expression of lupus

Masatoshi Wakui, Laurence Morel, Edward J. Butfiloski, Chunsun Kim, Eric S. Sobel

Research output: Contribution to journalArticle

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Abstract

Sle1 on chromosome 1 and Sle3/5 on chromosome 7 are two of the most critical lupus susceptibility loci of the New Zealand Black/White-derived NZM2410 mouse strain. In contrast to C57BL/6 mice congenic for either Sle1 (B6.Sle1) or Sle3/5 (B6.Sle3/5), strains that express only a modest lupus-related phenotype, the bicongenic B6.Sle1.Sle3/5 strain has a robust phenotype, suggesting a critical role for epistatic interactions in lupus pathogenesis. Mixed chimera experiments indicated that the two loci are functionally expressed by different cell populations and predicted that phenotypic expression of the phenotypic features of the B6.Sle1.Sle3/5 strain could be fully reproduced with a combination of B6.Sle1 and B6.Sle3/5 bone marrow. Contrary to our expectations, there was only a partial functional complementation in these mixed chimeras. Spleen enlargement, CD4:CD8 ratio elevation, and epitope spreading of autoantibodies were fully developed in B6+B6.Sle1.Sle3/5 but not in B6.Sle1+B6.Sle3/5 mixed chimeras. This study is the first to present evidence that the pathways mediated by two critical lupus susceptibility loci derived from the New Zealand White strain must be integrated intracellularly for epistatic interactions to occur. Our mixed chimera approach continues to provide novel insights into the functional genetic pathways underlying this important murine model of systemic autoimmunity.

Original languageEnglish
Pages (from-to)1337-1345
Number of pages9
JournalJournal of Immunology
Volume175
Issue number2
Publication statusPublished - 2005 Jul 15
Externally publishedYes

Fingerprint

Systemic Lupus Erythematosus
Dissection
New Zealand
Phenotype
CD4-CD8 Ratio
Chromosomes, Human, Pair 7
Chromosomes, Human, Pair 1
Autoimmunity
Inbred C57BL Mouse
Autoantibodies
Epitopes
Spleen
Bone Marrow
Population

ASJC Scopus subject areas

  • Immunology

Cite this

Genetic dissection of systemic lupus erythematosus pathogenesis : Partial functional complementation between Sle1 and Sle3/5 demonstrates requirement for intracellular coexpression for full phenotypic expression of lupus. / Wakui, Masatoshi; Morel, Laurence; Butfiloski, Edward J.; Kim, Chunsun; Sobel, Eric S.

In: Journal of Immunology, Vol. 175, No. 2, 15.07.2005, p. 1337-1345.

Research output: Contribution to journalArticle

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