C1q and Systemic Lupus Erythematosus

Walport, Mark; Davies, Kevin; Botto, Marina

doi:10.1016/s0171-2985(98)80032-6

Cited by 358 publications

(248 citation statements)

References 69 publications

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“…Of the C1q knockout mice ෂ25% develop glomerulonephritis with immune deposits and multiple apoptotic cell bodies in the glomeruli. 81,82 These findings are compatible with the theory that complement deficiency can contribute to autoimmunity, possibly by impairment of the clearance of apoptotic cells.…”

Section: Transgenics and Knockout Mice Models Of Lupussupporting

confidence: 86%

Immuno- and genetic therapy in autoimmune diseases

et al. 2000

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Animal models of autoimmune disease have been developed that mimic some aspects of the pathophysiology of human disease. These models have increased our understanding of possible mechanisms of pathogenesis at the molecular and cellular level and have been important in the testing, development and validation of new immunotherapies. The susceptibility to develop disease in the majority of these models is polygenic as is the case in humans. The exceptions to this rule are gene knock outs and transgenic models of particular genes which, in particular genetic backgrounds, have also contributed to the understanding of single gene function and their possible contribution to pathogenesis. Gene therapy approaches that target immune functions are being developed with encouraging results, despite the polygenic nature of these diseases. Basically this novel immuno-genetic therapy harnesses the knowledge of immunology with the myriad of biotechnological breakthroughs in vector design and delivery. Autoimmune disease is the result of genetic dysregulation which could be controlled by gene therapy. Here we summarize the genetic basis of these human diseases as well as some of the best characterized murine models. We discuss the strategies for their treatment using immunoand gene therapy. Genes and Immunity (2000) 1, 295-307.

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Section: Transgenics and Knockout Mice Models Of Lupussupporting

confidence: 86%

Immuno- and genetic therapy in autoimmune diseases

et al. 2000

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“…Of possible relevance to this study, deficiencies in early components of the complement cascade constitute strong, but rare, risk factors for susceptibility to SLE. In such cases, the male:female ratio is nearly equal (45). Given the propensity for abnormal CH50 levels (which is a measure of global complement component function) in our pedigrees with affected male relatives, analyses of candidate genes such as C1q, C2, C4, and related genes may provide at least a partial explanation for genetic susceptibility to SLE in this subset of families.…”

Section: Discussionmentioning

confidence: 96%

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

Stein

Olson

Gray‐McGuire

et al. 2002

Arthritis & Rheumatism

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Objective. To distinguish familial differences from sex-related differences in the clinical manifestations of systemic lupus erythematosus (SLE).Methods. A total of 372 affected individuals from 160 multiplex SLE pedigrees were analyzed. Twenty-five of these pedigrees contained at least 1 affected male relative. Comparisons of the presence of each of the 11 1982 American College of Rheumatology criteria for SLE were made between female family members with affected male relatives and those without affected male relatives, using Fisher's exact tests.Results. The presence of renal disease was significantly increased in female family members with an affected male relative when compared with those with no affected male relative (68% and 43%, respectively; P ‫؍‬ 0.002). This trend remained after stratifying by race and was most pronounced in European Americans. A familial basis for differences in hematologic and immunologic manifestations was also suggested, while arthritis and dermatologic features appeared to be most influenced by sex.Conclusion. Our results demonstrate that the increased prevalence of renal disease previously reported in men with SLE is, in large part, a familial rather than sex-based difference, at least in multiplex SLE families. Distinguishing familial from sex-related differences may facilitate efforts to understand the genetic and hormonal factors that underlie this complex autoimmune disease.

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“…In both humans and mice, a consequence of C1q deficiency is the development of a systemic lupus erythematosus-like syndrome. 23,32 However, in mice this is dependent on genetic background, since C1qa Ϫ/Ϫ animals show no evidence of autoimmunity after backcrossing onto C57BL/6. 33 The mice in our study failed to develop proteinuria, glomerulonephritis, or anti-ssDNA and did not have altered titers of antibodies to oxidized lipoproteins, suggesting that our results were not related to the development of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Bhatia

Yun

Leung

et al. 2007

The American Journal of Pathology

143

125

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We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa ؊/؊ ) with low-density lipoprotein receptor knockout mice (Ldlr ؊/؊ ). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa ؊/؊ /Ldlr ؊/؊ mice compared with Ldlr ؊/؊ mice (3.72 ؎ 1.0% aortic root versus 1.1 ؎ 0.4%; mean ؎ SEM , P < 0.001). Furthermore , the cellular composition of lesions in C1qa ؊/؊ / Ldlr ؊/؊ was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa ؊/؊ /Ldlr ؊/؊ mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa ؊/؊ /Ldlr ؊/؊ , whereas apoptotic cells were not detected in Ldlr ؊/؊ mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa ؊/؊ /Ldlr ؊/؊ mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis.

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C1q and Systemic Lupus Erythematosus

Cited by 358 publications

References 69 publications

Immuno- and genetic therapy in autoimmune diseases

Immuno- and genetic therapy in autoimmune diseases

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

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