Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: To determine the necessity for any individual BAFF receptor in the development of SLE.
Methods: NZM 2328 wild-type (WT), NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/-mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry, for serum BAFF and total IgG and IgG anti-dsDNA levels by ELISA, for glomerular deposition of IgG and C3 by immunofluorescence, for renal histopathology, and for clinical disease.
Results: The phenotypes of NZM mice deficient in a single BAFF receptor were highly divergent. In comparison to WT mice, NZM.Bcma-/- and NZM.Taci-/- mice harbored increased spleen B cells, T cells, and plasma cells (PC), whereas serum total IgG and IgG anti-dsDNA levels were similar to WT levels. Although B cells were markedly reduced in NZM.Br3-/- mice, they nonetheless harbored increased T cells as well as WT-like numbers of PC and levels of IgG anti-dsDNA. Serum BAFF levels were increased in NZM.Taci-/- and NZM.Br3-/- mice but were decreased in NZM.Bcma-/- mice. Expression of TACI on B cells and of BCMA and TACI on bone marrow (BM) PC was reduced in NZM.Br3-/- mice, and expression of BR3 and TACI on BM PC was markedly diminished in NZM.Taci-/- mice. Despite their phenotypic differences, renal immunopathology in NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/-mice, including robust glomerular deposition of IgG and C3 and development of glomerular hypercellularity, glomerular crescents, mesangial matrix deposition, interstitial inflammation and fibrosis, tubular atrophy, and perivascular leukocyte infiltration, was at least as severe as in WT mice. Moreover, clinical disease was indistinguishable among the four cohorts of mice. Severe proteinuria began to develop in each of the cohorts at 4-5 months of age, and ~90% of the mice in each cohort was affected by 12 months of age. Mortality in each of the cohorts was noted as early as 6-7 months of age, with ~90% of the mice in each cohort being dead by 12 months of age.
Conclusion: Any single BAFF receptor, including BR3, is dispensable to development of full-blown clinical SLE in NZM mice. The development of disease in NZM.Br3-/- mice demonstrates that BAFF/BCMA and/or BAFF/TACI interactions importantly contribute to SLE. Moreover, development of disease in NZM.Br3-/- mice demonstrates that profound, chronic reduction in B cells does not equate with protection from SLE. As such, NZM.Br3-/- mice may serve as a useful model in elucidating why the efficacy of B cell-depletion therapy in human SLE is limited.
C. O. Jacob,
W. J. Quinn III,
M. P. Cancro,
T. S. Migone,
Human Genome Sciences, Inc.,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-systemic-lupus-erythematosus-sle-in-nzm-2328-mice-in-the-absence-of-any-single-baff-receptor/