A central role for HLA-DR3 in anti-smith antibody responses and glomerulonephritis in a transgenic mouse model of spontaneous lupus

Vaidehi R. Chowdhary, Chao Dai, Ashenafi Y. Tilahun, Julie A. Hanson, Michele K. Smart, Joseph Peter Grande, Govindarajan Rajagopalan, Shu Man Fu, Chella S. David

Research output: Contribution to journalArticle

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Abstract

MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRb1∗0301) and devoid of endogenous class II (both I-A and I-E genes, AE0) on a lupus-prone NZM2328 background (NZM2328.DR3+AE0). Both NZM2328 and NZM2328.DR3+AE0 mice developed anti-dsDNA and glomerulonephritis, but antidsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3+AE0 mice (7.2 6 4.3 and 8.6 6 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3+AE0 mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p <0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3+AE0 mice. Interestingly, NZM2328.DR3+AE0 mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3+AE0 mice that were completely devoid of endogenous class II (AE-/-) but not in mice homozygous (AE+/+) or heterozygous (AE+/2) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4+ T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background.

Original languageEnglish (US)
Pages (from-to)4660-4667
Number of pages8
JournalJournal of Immunology
Volume195
Issue number10
DOIs
StatePublished - Nov 15 2015

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HLA-DR3 Antigen
Glomerulonephritis
Transgenic Mice
Antibody Formation
Anti-Idiotypic Antibodies
HLA-DR2 Antigen
Kidney
Lupus Nephritis
Linkage Disequilibrium
Genetic Predisposition to Disease
Autoimmunity
Proteinuria
Systemic Lupus Erythematosus
Alleles

ASJC Scopus subject areas

  • Immunology

Cite this

A central role for HLA-DR3 in anti-smith antibody responses and glomerulonephritis in a transgenic mouse model of spontaneous lupus. / Chowdhary, Vaidehi R.; Dai, Chao; Tilahun, Ashenafi Y.; Hanson, Julie A.; Smart, Michele K.; Grande, Joseph Peter; Rajagopalan, Govindarajan; Fu, Shu Man; David, Chella S.

In: Journal of Immunology, Vol. 195, No. 10, 15.11.2015, p. 4660-4667.

Research output: Contribution to journalArticle

Chowdhary, VR, Dai, C, Tilahun, AY, Hanson, JA, Smart, MK, Grande, JP, Rajagopalan, G, Fu, SM & David, CS 2015, 'A central role for HLA-DR3 in anti-smith antibody responses and glomerulonephritis in a transgenic mouse model of spontaneous lupus', Journal of Immunology, vol. 195, no. 10, pp. 4660-4667. https://doi.org/10.4049/jimmunol.1501073
Chowdhary, Vaidehi R. ; Dai, Chao ; Tilahun, Ashenafi Y. ; Hanson, Julie A. ; Smart, Michele K. ; Grande, Joseph Peter ; Rajagopalan, Govindarajan ; Fu, Shu Man ; David, Chella S. / A central role for HLA-DR3 in anti-smith antibody responses and glomerulonephritis in a transgenic mouse model of spontaneous lupus. In: Journal of Immunology. 2015 ; Vol. 195, No. 10. pp. 4660-4667.
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abstract = "MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRb1∗0301) and devoid of endogenous class II (both I-A and I-E genes, AE0) on a lupus-prone NZM2328 background (NZM2328.DR3+AE0). Both NZM2328 and NZM2328.DR3+AE0 mice developed anti-dsDNA and glomerulonephritis, but antidsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3+AE0 mice (7.2 6 4.3 and 8.6 6 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3+AE0 mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p <0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3+AE0 mice. Interestingly, NZM2328.DR3+AE0 mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3+AE0 mice that were completely devoid of endogenous class II (AE-/-) but not in mice homozygous (AE+/+) or heterozygous (AE+/2) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4+ T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background.",
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AU - Dai, Chao

AU - Tilahun, Ashenafi Y.

AU - Hanson, Julie A.

AU - Smart, Michele K.

AU - Grande, Joseph Peter

AU - Rajagopalan, Govindarajan

AU - Fu, Shu Man

AU - David, Chella S.

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