T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

Khalil, Magi; Inaba, Kayo; Steinman, Ralph M.; Ravetch, Jeffrey V.; Diamond, Betty

doi:10.4049/jimmunol.166.3.1667

Cited by 41 publications

(32 citation statements)

References 73 publications

(66 reference statements)

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“…BALB/c mice immunized with DWEYS-MAP develop T cell-dependent, anti-DNA/antipeptide, cross-reactive antibody responses (15,18). Using a tetrameric form of this peptide, we are able to detect the tetramer-reactive (Tet + ) compartment, which is enriched in DNA-reactive B cells (16,17).…”

Section: Rag Is Induced In Postactivation Early Memory/preplasma B Cementioning

confidence: 86%

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B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

Wang¹,

Diamond²

2008

J. Clin. Invest.

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Autoreactive B cells are regulated in the BM during development through mechanisms, including editing of the B cell receptor (BCR), clonal deletion, and anergy. Peripheral B cell tolerance is also important for protection from autoimmune damage, although the mechanisms are less well defined. Here we demonstrated, using a mouse model of SLE-like serology, that during an autoimmune response, RAG was reinduced in antigen-activated early memory or preplasma B cells. Expression of RAG was specific to antigen-reactive B cells, required the function of the IL-7 receptor (IL-7R), and contributed to maintenance of humoral tolerance. We also showed that soluble antigen could diminish a non-autoreactive antibody response through induction of BCR revision. These data suggest that tolerance induction operates in B cells at a postactivation checkpoint and that BCR revision helps regulate autoreactivity generated during an ongoing immune response.

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Section: Rag Is Induced In Postactivation Early Memory/preplasma B Cementioning

confidence: 86%

“…The antibody response is T cell dependent (18). In order to investigate the DNAreactive B cells participating in the response, we developed a methodology using a peptide tetramer to detect antigen-binding B cells in spleens of immunized mice.…”

Section: Figurementioning

confidence: 99%

B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

Wang¹,

Diamond²

2008

J. Clin. Invest.

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“…Calf thymus dsDNA was prepared according to the method described by Khalil et al (31). Briefly, calf thymus DNA (Sigma-Aldrich) was dissolved in PBS, sonicated, and filtered through a 0.45-m nitrocellulose Millex syringe filter (Millipore) to produce dsDNA in 10-20-kbp fragments.…”

Section: Methodsmentioning

confidence: 99%

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Hou¹,

He²,

Li³

et al. 2011

Arthritis & Rheumatism

111

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Objective. SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties. The aim of this study was to examine the effects and explore the mechanisms of SM934 to treat autoimmune disease in lupus-prone female MRL/lpr mice.Methods. In vitro, the effects of SM934 on the activation of polyclonal CD4؉ T cells and the differentiation of naive CD4؉ T cells were examined. In vivo, the preventative or therapeutic effects of SM934 in MRL/lpr mice were investigated. Ex vivo, the mechanisms of treatment were explored according to the immunologic correlates of disease.Results In female MRL/lpr mice, an autoimmune syndrome develops spontaneously that closely resembles human systemic lupus erythematosus (SLE) and is characterized by the production of various autoantibodies and the development of fatal glomerulonephritis (1,2).Disease begins as early as 8 weeks of age in these mice, with the presence of detectable serum autoantibodies. Pronounced lymphadenopathy is observed at 12 weeks of age, which is largely attributable to the accumulation of a population of B220ϩ and CD3ϩ cells that are mostly CD4Ϫ and CD8Ϫ (double-negative T cells). By 12-16 weeks of age, MRL/lpr mice begin to produce a variety of autoantibodies, including antidouble-stranded DNA (anti-dsDNA) antibodies. Multiple organs are affected, and a steady deterioration of renal function manifesting as severe proteinuria begins at approximately 16 weeks of age. From 16 weeks of age to 24 weeks of age, proliferative immune complex-

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“…There are increasing data, from a variety of experimental systems, where generation of T reg cells has been impaired, implicating T reg cells in the regulation of lupus autoantibody production (26,33). In studies demonstrating a T cell-dependent loss of B cell tolerance to chromatin/ dsDNA by normal B cells, tolerant B cells were experimentally manipulated to present nonself-peptides to T cells, thus evading normal T cell tolerance mechanisms (30,31). In one of these experimental systems, addition of T reg cells prevented differentiation of chromatin/dsDNA B cells into Ab-forming cells as well as entry into germinal centers (31).…”

Section: Discussionmentioning

confidence: 99%

Functional Interplay between Intrinsic B and T Cell Defects Leads to Amplification of Autoimmune Disease in New Zealand Black Chromosome 1 Congenic Mice

Cheung

Chang

Cai

et al. 2005

The Journal of Immunology

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Genetic loci on New Zealand Black (NZB) chromosome 1 play an important role in the development of lupus-like autoimmune disease. We have shown previously that C57BL/6 mice with an introgressed NZB chromosome 1 interval extending from ∼35 to 106 cM have significantly more severe autoimmunity than mice with a shorter interval extending from ∼82 to 106 cM. Comparison of the cellular phenotype in these mice revealed that both mouse strains had evidence of increased T cell activation; however, activation was more pronounced in mice with the longer interval. Mice with the longer interval also had increased B cell activation, leading us to hypothesize that there were at least two independent lupus susceptibility loci on chromosome 1. In this study, we have used mixed hemopoietic radiation chimeras to demonstrate that autoimmunity in these mice arises from intrinsic B and T cell functional defects. We further show that a T cell defect, localized to the shorter interval, leads to spontaneous activation of T cells specific for nucleosome histone components. Despite activation of self-reactive T cells in mixed chimeric mice, only chromosome 1 congenic B cells produce anti-nuclear Abs and undergo class switching, indicating impaired B cell tolerance mechanisms. In mice with the longer chromosome 1 interval, an additional susceptibility locus exacerbates autoimmune disease by producing a positive feedback loop between T and B cell activation. Thus, T and B cell defects act in concert to produce and amplify the autoimmune phenotype.

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T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

Cited by 41 publications

References 73 publications

B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Functional Interplay between Intrinsic B and T Cell Defects Leads to Amplification of Autoimmune Disease in New Zealand Black Chromosome 1 Congenic Mice

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