Protection of Murine Lupus by the<i>Ea</i>d Transgene Is MHC Haplotype-Dependent

Ibnou-Zekri, Nabila; Iwamoto, Masahiro; Gershwin, M. Eric; Izui, Shozo

doi:10.4049/jimmunol.164.1.505

Cited by 15 publications

(16 citation statements)

References 33 publications

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“…These results are in agreement with our recent demonstration that the level of protection conferred by Ea-Tg is highly dependent on the host weakest with the H2 d haplotype (17). It should also be stressed that the autoimmune inhibitory effect mediated by the Ea-Tg is dependent on the type of autoimmune responses.…”

Section: Discussionsupporting

confidence: 82%

“…This could occur as a result of increased formation of peptides derived from the transgenic E␣-chains, as an E␣ 52-68 peptide has been identified as one of the major self-peptides presented by I-A b and I-A d molecules (15,16). The hypothesis that the action of the transgene is mediated through the interaction of its products with the MHC class II molecules, thus competing with potentially pathogenic selfpeptides, was further supported by a recent demonstration that the transgene effect is highly dependent on the host H2 haplotype (17).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 65%

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Epitope-Dependent Inhibition of T Cell Activation by theEaTransgene: An Explanation for Transgene-Mediated Protection from Murine Lupus

Martinez-Soría

Ibnou-Zekri

Iwamoto

et al. 2004

The Journal of Immunology

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A high level expression of the Ead transgene encoding the I-E α-chain is highly effective in the suppression of lupus autoantibody production in mice. To explore the possible modulation of the Ag-presenting capacity of B cells as a result of the transgene expression, we assessed the ability of the transgenic B cells to activate Ag-specific T cells in vitro. By using four different model Ag-MHC class II combinations, this analysis revealed that a high transgene expression in B cells markedly inhibits the activation of T cells in an epitope-dependent manner, without modulation of the I-E expression. The transgene-mediated suppression of T cell responses is likely to be related to the relative affinity of peptides derived from transgenic I-E α-chains (Eα peptides) vs antigenic peptides to individual class II molecules. Our results support a model of autoimmunity prevention based on competition for Ag presentation, in which the generation of large amounts of Eα peptides with high affinity to I-A molecules decreases the use of I-A for presentation of pathogenic self-peptides by B cells, thereby preventing excessive activation of autoreactive T and B cells.

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Section: Discussionsupporting

confidence: 82%

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 65%

Epitope-Dependent Inhibition of T Cell Activation by theEaTransgene: An Explanation for Transgene-Mediated Protection from Murine Lupus

Martinez-Soría

Ibnou-Zekri

Iwamoto

et al. 2004

The Journal of Immunology

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“…For these reasons, OPN locus might not be detected. Kono et al [6] used (BXSB Â NZW)F 2 with a different MHC haplotype combination (H-2 b and H-2 z , respectively), which might affect the difference of set of susceptibility loci possibly influenced by MHC [18]. These may be the reason why previous studies did not conclude that a locus for autoimmune diseases including glomerulonephritis and vasculitis shares a chromosomal region with Agnm3.…”

Section: Discussionmentioning

confidence: 99%

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Miyazaki

Ono

et al. 2005

Eur J Immunol

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Potentially, autoimmune diseases develop from a combination of multiple genes with allelic polymorphisms. An MRL/Mp-Fas lpr/lpr (MRL/lpr) strain of mice develops autoimmune diseases, including lupus nephritis, but another lpr strain, C3H/HeJFas lpr/lpr (C3H/lpr) does not. This indicates that MRL polymorphic genes are involved in the development of the diseases. By quantitative trait loci (QTL) analysis using 527 of the (MRL/lpr Â C3H/lpr)F 2 mice, we identified a novel locus for susceptibility to lupus nephritis at map position D5Mit115 on chromosome 5, the same alias of the osteopontin (Opn) gene (LOD score =4.0), susceptible in the MRL allele. In functional analyses of the MRL and C3H Opn alleles using synthetic osteopontin (OPN) made with a new method "cell-free system" with wheat germ ribosomes, the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-a, IL-1b and IFN-c in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis.

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“…In various murine autoimmune disease models, CD4 ϩ T cell responses to self-MHC Ags have been related to suppression of the disease (13,14). In addition, MHC-derived peptides constitute a large fraction of the natural ligands eluted from MHC class II molecules (15).…”

Section: P Redisposition To Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs

Snijders

Elferink

Geluk

et al. 2001

The Journal of Immunology

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Predisposition to rheumatoid arthritis (RA) is thought to be associated with HLA-DR1, -DR4, and -DR10. However, many epidemiological observations are better explained by a model in which the DQ alleles that are linked to these DR alleles, i.e., DQ5, DQ7, and DQ8, predispose to RA, while certain DR alleles have a dominant protective effect. All protective DRB1 alleles, e.g., *0402, *1301, and *1302, encode a unique motif, 70DERAA74. The protection may be explained by the presentation of DRB1-derived peptides by DQ to immunoregulatory T cells, because it was demonstrated in various autoimmune disease models that T cell responses to certain self-Ags can be involved in disease suppression. The aim of this study was to analyze whether peptides carrying the DERAA motif are naturally processed by human APC and presented in the context of the RA-predisposing DQ. Using a synthetic peptide carrying the DRB1*0402-derived sequence 65KDILEDERAAVDTYC79, we generated DERAA peptide-specific DQ-restricted T cell clones (TCC) from a DQ8 homozygous individual carrying DERAA-negative DR4 alleles. By analyzing the proliferation of these TCC, we demonstrated natural processing and presentation of the DERAA sequence by the APC of all the individuals (n = 12) carrying a DERAA-positive DRB1 allele and either DQ8 or the DQ8-related DQ7. Using a panel of truncated synthetic peptides, we identified the sequence 67(I)LEDERAAVD(TY)78 as the minimal determinant for binding to DQ8 and for recognition by the TCC. These findings support a model in which self-MHC-derived peptide can modulate predisposition to autoimmune disease in humans.

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Protection of Murine Lupus by theEad Transgene Is MHC Haplotype-Dependent

Cited by 15 publications

References 33 publications

Epitope-Dependent Inhibition of T Cell Activation by theEaTransgene: An Explanation for Transgene-Mediated Protection from Murine Lupus

Epitope-Dependent Inhibition of T Cell Activation by theEaTransgene: An Explanation for Transgene-Mediated Protection from Murine Lupus

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs

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