The E-linked subregion of the major histocompatability complex down-regulates autoimmunity in NZB x NZW F1 mice

Hirose, Sachiko; Zhang, Danqing; Nozawa, Shingo; Nishimura, Hiroyuki; Shirai, Toshikazu

doi:10.1007/bf00188179

Cited by 19 publications

(14 citation statements)

References 14 publications

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“…With regard to this difference, other investigators have observed partial prevention of mouse lupus in mice with high levels of I-E expression (24,32,33). Studies have suggested that peptides derived from I-E d and I-E z can prevent autoantibody production, perhaps through blocking of I-A presentation of other self peptides (24,(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Effects of MHC and Gender on Lupus-Like Autoimmunity inNba2Congenic Mice

Gubbels

Jørgensen

Metzger³

et al. 2005

The Journal of Immunology

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The lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC- and non-MHC-encoded genes. Studies in this model have indicated that the H2d/z MHC type, compared with H2d/d or H2z/z, is critical for disease development. C57BL/6 (B6) mice (H2b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6.Nba2 to NZW results in H2b/z F1 offspring that develop severe lupus nephritis. Despite the importance of H2z in past studies, we found no enhancement of autoantibody production or nephritis in H2b/z vs H2b/b B6.Nba2 mice, and inheritance of H2z/z markedly suppressed autoantibody production. (B6.Nba2 × NZW)F1 mice, compared with MHC-matched B6.Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F1 mice, kidneys of some B6.Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6.Nba2 and F1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.

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Section: Discussionmentioning

confidence: 99%

Effects of MHC and Gender on Lupus-Like Autoimmunity inNba2Congenic Mice

Gubbels

Jørgensen

Metzger³

et al. 2005

The Journal of Immunology

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“…Because the expression of two copies of the Ea gene is capable of providing protection from SLE (8,9,32), the possible role of the MHC class II Ea gene as a lupus-protective gene in mice is likely to be influenced by the host MHC haplotype. However, it should be stressed that the effect of the Ea d transgene can be modulated by genetic factors other than the MHC class II genes present in the genetic background of individual lupus-prone mice.…”

Section: Discussionmentioning

confidence: 99%

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

Ibnou-Zekri

Iwamoto

Gershwin

et al. 2000

The Journal of Immunology

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A high-level expression of a transgene, Ead, encoding the I-Ed α-chain is very effective in protection against murine lupus. To investigate the specific contribution of select H-2 haplotypes on the Ead transgene-mediated disease-suppressing effect, we generated H-2 congenic (NZB × BXSB)F1 hybrid mice bearing either H-2b/b, H-2d/b, or H-2d/d haplotype, and compared the transgene-mediated protective effect on the clinical development (autoantibody production and glomerulonephritis) of lupus in these F1 hybrids. The level of protection was most remarkable in mice bearing the I-E− H-2b/b haplotype but was only minimal in I-E+ H-2d/d F1 hybrids. Additional analysis demonstrated a marked suppression of lupus in I-E+ H-2k/k (MRL × BXSB)F1 hybrid mice, indicating that the transgene is able to suppress autoimmune responses even in mice already expressing I-E molecules at a homozygous level. Our results indicate that the level of the transgene-mediated protection is dependent on the host H-2 haplotype. This suggests that the autoimmune suppressive activity of the Ead transgene is likely to be determined through the interaction of the transgene product with the host MHC class II molecules, providing new insight into the role of MHC in lupus-like autoimmunity.

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“…§ The additional microsatellite markers used in this study, in comparison with the previous study (28), are D1Mit50 (1,52), D1Mit115 (1, 97), D1Mit115 (1,108), D4Mit72 (4,62), D4Mit179 (4,69), D4Mit343 (4,76), D7Mit125 (7,50), D13Mit73 (13,53), D16Mit57 (16,14), D19Mit28 (19,12), D19Mit13 (19,33), and DXMit16 (X,42).…”

Section: Identification Of Nzb and Nzw Loci Linked With Nephritismentioning

confidence: 99%

Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice.

et al. 1996

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F 1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice are a model of human systemic lupus erythematosus. These mice develop a severe immune complex-mediated nephritis, in which antinuclear autoantibodies are believed to play the major role. We used a genetic analysis of (NZB ϫ NZW)F 1 ϫ NZW backcross mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin, which overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein, gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a distal chromosome 4 locus, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production. (J. Clin. Invest. 1996. 98:1762-1772.)

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The E-linked subregion of the major histocompatability complex down-regulates autoimmunity in NZB x NZW F1 mice

Cited by 19 publications

References 14 publications

Effects of MHC and Gender on Lupus-Like Autoimmunity inNba2Congenic Mice

Effects of MHC and Gender on Lupus-Like Autoimmunity inNba2Congenic Mice

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

Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice.

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