The candidate gene approach: have murine models informed the study of human SLE?

Graham, Deborah S. Cunninghame

doi:10.1111/j.1365-2249.2004.02525.x

Cited by 12 publications

(3 citation statements)

References 79 publications

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“…In a recent genome wide study and directed SNP analyses, there was an association between specific SNPs in the fH gene and the development of lupus (44). Although there are clearly differences in the human vs. mouse complement systems and in human vs. mouse lupus, the vast majority of pathogenic factors implicated in human lupus were first discovered in murine models or confirmed in murine models (45). …”

Section: Discussionmentioning

confidence: 99%

The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice

Sekine¹,

Kinser²,

Qiao³

et al. 2011

Arthritis & Rheumatism

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Objective. Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. The aim of this study was to investigate the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice.Methods. Mice were treated with either saline, CR2-fH, CR2-Crry (which inhibits all complement pathways), or soluble CR2 (sCR2; C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs, and C3. Urinary excretion of albumin was also determined, and kidneys were collected at 23 weeks for histologic evaluation.Results. Treatment with CR2-fH or CR2-Crry improved survival and significantly reduced proteinuria, glomerular C3 deposition, and the level of circulating ICs. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, expression of serum antidouble-stranded DNA (anti-dsDNA) antibodies, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced the levels of anti-dsDNA antibodies and circulating ICs and reduced glomerular deposition of IgG, C1q, and C3, although there was no significant reduction in glomerulonephritis, proteinuria, or mortality.Conclusion. Targeted and selective inhibition of the alternative complement pathway is an effective treatment of murine lupus and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact and indicate distinct roles for the classical and alternative pathways of complement in disease progression. The sCR2-targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.The complement system can be activated by 1 of 3 pathways (classical, lectin, and alternative) and provides important host defense, homeostasis, and immune regulatory functions. However, the complement system also plays a pathogenic role in many autoimmune and inflammatory diseases, including systemic lupus erythematosus (SLE) (1). SLE is the prototypic human autoimmune disease, and complement-mediated injury is initiated by immune complexes (ICs) formed by autoantibodies directed against a broad range of self antigens (2,3). The kidney is a major site of immune complex formation and/or deposition, and lupus nephritis is a major cause of morbidity and mortality, in both human SLE and murine models of lupus. There is, however, an apparent dual role for complement in the development and progression of lupus, as highlighted by the different roles of the classical and alternative complement pathways in the disease.Patients with homozygous deficiencies of early Supported by grants from the US Department of Defense (W81 XWH-07-1-0161) and the NIH (HL-082485).

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Section: Discussionmentioning

confidence: 99%

The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice

Sekine¹,

Kinser²,

Qiao³

et al. 2011

Arthritis & Rheumatism

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“…Other interesting mouse knockout models that develop autoimmune phenotypes include those for C1Q [ 62 ], Fcγ [ 63 ], and Toll-like receptor-7 [ 64 ]. Mapping of the genes responsible for disease in spontaneous models of lupus in mice is another area of active interest, and the overlap between the search for autoimmune genes in human and mouse is due to expand and integrate rapidly as new technologies are brought to bear on this area [ 51 ].…”

Section: Specific Genes Associated With Systemic Lupus Erythematosusmentioning

confidence: 99%

Current status of lupus genetics

et al. 2007

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Over the past 40 years more than 100 genetic risk factors have been defined in systemic lupus erythematosus through a combination of case studies, linkage analyses of multiplex families, and case-control analyses of single genes. Multiple investigators have examined patient cohorts gathered from around the world, and although we doubt that all of the reported associations will be replicated, we have probably already discovered many of the genes that are important in lupus pathogenesis, including those encoding human leukocyte antigen-DR, Fcγ receptor 3A, protein tyrosine phosphatase nonreceptor 22, cytotoxic T lymphocyte associated antigen 4, and mannose-binding lectin. In this review we will present what is known, what is disputed, and what remains to be discovered in the world of lupus genetics. IntroductionSystemic lupus erythematosus (SLE) has long been appreciated to arise from both genetic and environmental factors. Although environmental factors, such as the EpsteinBarr virus, are clearly important [1], this review focuses on genetic factors that are involved in SLE. Evidence for the genetic origins of the disease come from the observation of familial aggregation [2] (up to 10% of patients with SLE have another family member with the disease) and increased concordance in monozygotic twins [3]. The patterns of inheritance are complex, however, and it is generally thought that variations in a number of genes are involved, each contributing a small amount to the overall genetic risk [4]. Two major strategies have been used to search for the 'lupus genes': genome-wide screening, using multiplex families and linkage analysis; and candidate gene studies, usually performed on trios or case-control collections. With either strategy, a high threshold is necessary to establish genetic risk, and follow-up testing of an independent cohort is required to confirm the results. Genome-wide linkage studies for systemic lupus erythematosusThe genetic basis of SLE is well established, but the genetic transmission of SLE has proven to be highly complex. Consequently, gene identification has been accomplished for only a handful of genes. Genome-wide linkage scanning is a comprehensive and unbiased approach to identifying chromosomal loci that may be linked to complex diseases [5]. Testing for genome-wide linkage is fundamentally a statistical process that evaluates for co-inheritance of genetic markers (such as DNA polymorphisms) with the disease phenotype in families with multiple affected members. Consistent coinheritance of the marker with the disease in families means that they are 'linked' and indicates that the actual disease gene is in close proximity. As with other complex diseases, genome scans for SLE susceptibility genes suffer from low power to detect true-positive linkages. Causes of this include relatively small study populations in some studies and common causative alleles with low penetrance.Several different study designs have been used for genomewide scanning to identify novel susceptibility loci for...

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“…While considerable effort has gone into trying to understand the immune dysfunctions leading to renal involvement with many new treatments (discussed in [ 14 ]), our understanding of target organ resistance to immune insults is less well defined. However, murine models of SLE can likely provide useful information regarding human disease (reviewed in [ 17 , 18 ]).…”

Section: Introductionmentioning

confidence: 99%

Sex-specific effects of LiCl treatment on preservation of renal function and extended life-span in murine models of SLE: perspective on insights into the potential basis for survivorship in NZB/W female mice

Hart

2016

Biol Sex Differ

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Considerable research effort has been invested in attempting to understand immune dysregulation leading to autoimmunity and target organ damage. In systemic lupus erythematosus (SLE), patients can develop a systemic disease with a number of organs involved. One of the major target organs is the kidney, but patients vary in the progression of the end-organ targeting of this organ. Some patients develop glomerulonephritis only, while others develop rapidly progressive end organ failure. In murine models of SLE, renal involvement can also occur. Studies performed over the past several years have indicated that treatment with LiCl of females, but not males of the NZB/W model, at an early age during the onset of disease, can prevent development of end-stage renal disease in a significant percentage of the animals. While on Li treatment, up to 80 % of the females can exhibit long-term survival with evidence of mild glomerulonephritis which does not progress to renal failure in spite of on-going autoimmunity. Stopping the treatment led to a reactivation of the disease and renal failure. Li treatment of other murine models of SLE was less effective and decreased survivorship in male BxSB mice, exhibited little effect on male MRL-lpr mice, and only modestly improved survivorship in female MRL-lpr mice. This perspective piece discusses the findings of several related studies which support the concept that protecting target organs such as the kidney, even in the face of continued immune insults and some inflammation, can lead to prolonged survival with retention of organ function. Some possible mechanisms for the effectiveness of Li treatment in this context are also discussed. However, the detailed mechanistic basis for the sex-specific effects of LiCl treatment particularly in the NZB/W model remains to be elucidated. Elucidating such details may provide important clues for development of effective treatment for patients with SLE, ~90 % of which are females.

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The candidate gene approach: have murine models informed the study of human SLE?

Cited by 12 publications

References 79 publications

The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice

The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice

Current status of lupus genetics

Sex-specific effects of LiCl treatment on preservation of renal function and extended life-span in murine models of SLE: perspective on insights into the potential basis for survivorship in NZB/W female mice

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