Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: Large genome wide scans have confirmed the strong association of HLA -DR3 with risk of developing SLE and antibody response to Sm which is specific to lupus. To understand the role of HLA-DR3 in pathogenesis of lupus and anti- Sm response, we generated NZM2328 mice transgenically expressing HLA-DR3 and devoid of endogenous mouse class II (AE0). Female NZM2328 spontaneously develop anti-dsDNA and severe glomerulonephritis whereas incidence of glomerulonephritis is less in male mice.
Methods: HLA DR3.AE0 transgenic mice were repeatedly backcrossed to NZM2328 mice for 6 generations. Mice were genotyped by PCR and Flow cytometry. Various cohorts of mice were followed monthly for proteinuria using Albustix and sera collected. Urinary protein greater than 300 mg/dL (3+ or more) was considered significant. Anti-Sm antibodies were determined by ELISA and immunoprecipitation.
The overall incidence of proteinuria in female NZM2328.DR3+.AE0 and NZM2328 mice at 12 months was 58% and 62% respectively (p=0.38) whereas male mice, as expected, had low incidence of proteinuria namely 11% in NZM2328 and 19% in NZM2328.DR3+.AE0. No proteinuria was seen in DR3+ .AE0 and AE0 mice. Both NZM2328 and NZM2328.DR3+.AE0 developed anti-dsDNA antibodies. NZM2328 males and females, AE0 and DR3+AE0 mice did not develop anti-Sm antibodies whereas both male and female NZM2328.DR3+.AE0 mice developed anti-Sm antibodies. Preliminary results from immunoprecipitation in few samples also confirm presence of anti-Sm antibody in NZM2328.DR3+.AE0 mice. These mice develop glomerulonephritis and kidney scores are shown in Table 1.
Total number of spleen cells, CD4+, CD8+, B220+ and Mac1+ cells were enumerated in NZM2328, NZM2328.DR3+ AE0 mice and were not significantly different. Similarly the total numbers of thymocytes, CD4, CD8 double negative, double positive, single positives were also not different in both the groups. Certain CD4+, CD8+ T cell Vβ families were increased in NZM2328 and NZM2328. DR3+.AE0 mice compared to DR3+AE0 mice.
These results strongly support that that HLA-DR3, in an autoimmune prone background, plays an important role in generating an immune response to Sm and development of glomerulonephritis.
V. R. Chowdhary,
S. M. Fu,
C. S. David,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-dr3-controls-autoantibody-response-to-sm-in-nzm2328-dr3-ae0-transgenic-mice/