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Characterization of reciprocal Lmb1-4 interval MRL-Faslpr and B6-Faslpr congenic mice reveals significant effects from Lmb3
Umeå University, Faculty of Medicine, Clinical Microbiology, Immunology/Immunchemistry.
Umeå University, Faculty of Medicine, Clinical Microbiology, Immunology/Immunchemistry.
2007 (English)In: Journal of immunology, ISSN 0022-1767, Vol. 178, no 12, 8195-8202 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2007. Vol. 178, no 12, 8195-8202 p.
URN: urn:nbn:se:umu:diva-3018OAI: diva2:141446
Available from: 2008-03-17 Created: 2008-03-17Bibliographically approved
In thesis
1. Defining the genetics of systemic autoimmunity in mouse models of lupus
Open this publication in new window or tab >>Defining the genetics of systemic autoimmunity in mouse models of lupus
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic Lupus Erythematosus (SLE) is a chronic multi-organ autoimmune disease considered a prototype for autoantibody and immune complex-mediated tissue injury. Although autoantibodies against a wide diversity of self-antigens are characteristically found in this disease, an important hallmark is the presence of autoantibodies to nuclear antigens. Despite this common clinical feature, individual patients vary widely in the organ systems afflicted, disease severity, disease course, and response to treatment. These characteristics make clinical management of SLE challenging and highlight the need for effective and less toxic therapeutic interventions.

Susceptibility to lupus has been shown in both human studies and mouse models to be dependent on genetic predisposition. Therefore, it is likely that knowledge of the genetic basis of SLE will be required before full understanding of SLE pathogenesis can be achieved. In this thesis, studies to define the genetic basis of lupus in an induced and two spontaneous models of the disease are presented. These studies encompass mapping, characterization of interval congenic mice, and cloning of the Lmb3 locus gene. In the first study, a genomewide mapping study was performed to define the genetic basis for resistance of the DBA/2 mice to mercury-induced autoimmunity. On chromosome 1, a single quantitative trait was linked with resistance to HgIA. These results linked the locus Hmr1 to a late stage of lupus with GN. Interval congenic mice are important tools to define and characterize the roles of different loci in lupus-like diseases. The second paper identifies the effect of NZB and NZW Lbw2 alleles on lupus susceptibility by using BWF1 mice with none, one or two copies of the lupus-predisposing NZB.Lbw2 locus. The lack of the NZB locus significantly reduced mortality, GN and B cell activation. IgM anti-chromatin levels in genome-wide mapping was linked only to Lmb2 and none of the known B cell hyperactivity-promoting genes were present in this location, which might indicate a novel B cell activation gene. The third study used reciprocal single locus interval-specific congenic mice to characterize the contribution of Lmb1-4 on the MRL-Faslpr and B6-Faslpr backgrounds. The Lmb3 locus on chromosome 7 was found to have the most prominent phenotype with clear effects on lymphoproliferation, GN and mortality. In the fourth paper the Lmb3 was cloned and shown to be a spontaneous nonsense mutation in the Coro1a gene that encodes an actin-binding and -regulatory protein. Upon further characterization, this genetic alteration was discovered to be a new lupus suppressing mutation that reduced T cell migration, activation, and survival. Our findings highlight the complexity of the genetics of lupus, and further suggest that genes involved in controlling the actin cytoskeleton might be potential targets for autoimmune therapeutics.

Place, publisher, year, edition, pages
Umeå: Immunologi/immunkemi, 2008. 75 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1169
SLE, susceptibility, HgIA, genome-wide mapping, Lbw2, Lmb1-4, suppressing gene
National Category
urn:nbn:se:umu:diva-1584 (URN)978-91-7264-540-0 (ISBN)
Public defence
2008-04-02, E04, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2008-03-17 Created: 2008-03-17 Last updated: 2009-04-29Bibliographically approved

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