Defining the genetics of systemic autoimmunity in mouse models of lupus

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 t...

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Main Author: Haraldsson, Katarina
Format: Doctoral Thesis
Language:English
Published: Umeå universitet, Immunologi/immunkemi 2008
Subjects:
SLE
Online Access:http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1584
http://nbn-resolving.de/urn:isbn:978-91-7264-540-0
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spelling ndltd-UPSALLA1-oai-DiVA.org-umu-15842013-01-08T13:05:06ZDefining the genetics of systemic autoimmunity in mouse models of lupusengHaraldsson, KatarinaUmeå universitet, Immunologi/immunkemiUmeå : Immunologi/immunkemi2008SLEsusceptibilityHgIAgenome-wide mappingLbw2Lmb1-4suppressing geneImmunologyImmunologiSystemic 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. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1584urn:isbn:978-91-7264-540-0Umeå University medical dissertations, 0346-6612 ; 1169application/pdfinfo:eu-repo/semantics/openAccess
collection NDLTD
language English
format Doctoral Thesis
sources NDLTD
topic SLE
susceptibility
HgIA
genome-wide mapping
Lbw2
Lmb1-4
suppressing gene
Immunology
Immunologi
spellingShingle SLE
susceptibility
HgIA
genome-wide mapping
Lbw2
Lmb1-4
suppressing gene
Immunology
Immunologi
Haraldsson, Katarina
Defining the genetics of systemic autoimmunity in mouse models of lupus
description 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.
author Haraldsson, Katarina
author_facet Haraldsson, Katarina
author_sort Haraldsson, Katarina
title Defining the genetics of systemic autoimmunity in mouse models of lupus
title_short Defining the genetics of systemic autoimmunity in mouse models of lupus
title_full Defining the genetics of systemic autoimmunity in mouse models of lupus
title_fullStr Defining the genetics of systemic autoimmunity in mouse models of lupus
title_full_unstemmed Defining the genetics of systemic autoimmunity in mouse models of lupus
title_sort defining the genetics of systemic autoimmunity in mouse models of lupus
publisher Umeå universitet, Immunologi/immunkemi
publishDate 2008
url http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1584
http://nbn-resolving.de/urn:isbn:978-91-7264-540-0
work_keys_str_mv AT haraldssonkatarina definingthegeneticsofsystemicautoimmunityinmousemodelsoflupus
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