Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells

Pan, Zijian; Maier, Shannon; Schwarz, Karen; Azbill, Jennifer; Akira, Shizuo; Uematsu, Satoshi; Farris, A. Darise

doi:10.1136/ard.2009.108282

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…These animals also have a milder kidney disease [34]. A similar effect of TLR‐7‐deficiency was observed in pristane‐induced SLE [35,36], and in glomerular injury induced with syngeneic late apoptotic cells [37].…”

Section: Tlr‐7 and ‐9: In Vivo Studiesmentioning

confidence: 57%

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

Lenert

2010

Clinical and Experimental Immunology

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Section: Tlr‐7 and ‐9: In Vivo Studiesmentioning

confidence: 57%

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

Lenert

2010

Clinical and Experimental Immunology

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“…Thus, little genetic change is needed to transform B6 mice producing harmless IgG ANA into an autoimmune disease prone mouse strain. Furthermore, young wild‐type B6 mice produce IgG autoantibodies against dsDNA and histones in an MyD88‐dependent manner after immunization with syngeneic late apoptotic thymocytes . The role of MyD88 in the spontaneous IgG ANA production, that we report here, remains to be established…”

Section: Discussionmentioning

confidence: 80%

The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T‐cell compartment

et al. 2014

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Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8-12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4 + T-cell dependent, since old (40-50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age-related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4 + T cells that promote ANA production were radioresistant.Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T-cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T-cell homeostasis may drive the onset of some autoimmune features.Keywords: Antinuclear antibody r Autoimmunity r Sjögren's syndrome r T-cell homeostasis See accompanying Commentary by Winkler and WaismanAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt is well established that the functional activity of the immune system declines with age. The fact that mortality and morbidity during annual influenza epidemics increases in the elderly population is a clear example of this [1]. Moreover, influenza vaccinations are only marginally protective for the elderly [2][3][4]. Yet another example of immune activity decline with age is the reactivation of the Varicella zoster virus in the elderly. The frequency of this reactivation increases in individuals after the fiftieth year [5] and is thought to be due to a generalized decreased memory response to Correspondence: Prof. Antonius Rolink e-mail: antonius.rolink@unibas.ch chronic infections. In addition, some malignancies are more often found among the elderly [6]. For multiple myeloma, the median age of diagnosis is 66 years and only 2% of all patients are younger than 40 years of age. The increased incidence of this plasma cell tumor and of certain other malignancies with age might suggest that, in these cases, immune surveillance is effective in young individuals, but declines with age. The decline in immune competence is thought to be due to an age-related decrease in production of both B cells and T cells. We and others have shown that in both mouse and man, B-cell production decreases with age [7][8][9]. Thus, the frequency of mouse BM derived pro-B cells, which can be grown on stromal cells in the presence of IL-7, decreases with age: from a frequency of around 1 in 50 at 2 weeks of age, whereas this frequency drops to 1 in C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2894 Anja Nusser et al. Eur. J. Immunol. 2014. 44: 2893-2902...

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“…Images were acquired using Zeiss Axiovert 200M inverted fluorescent microscope and AxioVision software. Glomerular IgG and C3 depositions were quantified as described (41). In brief, 5 Blk+/+ , 5 Blk+/− and 3 Blk−/− female mice at 1 yr of age were used.…”

Section: Methodsmentioning

confidence: 99%

Concordance of Increased B1 Cell Subset and Lupus Phenotypes in Mice and Humans Is Dependent on BLK Expression Levels

Georg

Díaz-Barreiro

et al. 2015

The Journal of Immunology

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Polymorphisms in the BLK gene have been associated with autoimmune diseases, including systemic lupus erythematosus (SLE), with risk correlating with reduced expression of BLK. How reduced expression of BLK causes autoimmunity is unknown. Using Blk+/+, Blk+/−, and Blk−/− mice, we show that aged female Blk+/− and Blk−/− mice produced higher anti-dsDNA IgG antibodies and developed immune complex-mediated glomerulonephritis, compared to Blk+/+ mice. Starting at young age, Blk+/− and Blk−/− mice accumulated increased numbers of splenic B1a cells, which differentiated into class-switched CD138+IgG-secreting B1a cells. Increased infiltration of B1a-like cells into the kidneys was also observed in aged Blk+/− and Blk−/− mice. In human, we found that healthy individuals had BLK genotype-dependent levels of anti-dsDNA IgG antibodies as well as increased numbers of a B1-like cell population, CD19+CD3−CD20+CD43+CD27+, in peripheral blood. Furthermore, we describe the presence of B1-like cells in the tubulointerstitial space of human lupus kidney biopsies. Taken together, our study reveals a previously unappreciated role of reduced BLK expression on extraperitoneal accumulation of B1a cells in mice, and the presence of IgG autoantibodies and B1-like cells in human.

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Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells

Cited by 12 publications

References 38 publications

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T‐cell compartment

Concordance of Increased B1 Cell Subset and Lupus Phenotypes in Mice and Humans Is Dependent on BLK Expression Levels

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Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells

Cited by 12 publications

References 38 publications

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4+ T‐cell compartment

Concordance of Increased B1 Cell Subset and Lupus Phenotypes in Mice and Humans Is Dependent on BLK Expression Levels

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The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T‐cell compartment