Session Type: Poster Session D
Session Time: 1:00PM-3:00PM
Background/Purpose: Sle1 and FASlpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus (SLE) by altering the FAS/FASL pathway and adaptive immunity. Although C57BL/6 (B6) mice bearing either of these genes display mild phenotypes, the epistatic interaction of Sle1 and FASlpr results in severe lupus, confirming that these two genes impact non-redundant, pathways. Here, we aim to evaluate whether FASlpr exhibits gene dosage effects in determining cellular and serological phenotypes associated with lupus.
Methods: B6, B6.FASlpr/lpr (lprhomo), B6.Sle1/Sle1 (sle1), B6.Sle1/Sle1.FASlpr/+ (sle1.lprhet), and B6.Sle1/Sle1.FASlpr/lpr (sle1.lprhomo) mice were bred and examined at three different ages: 2-3 month (mo), 4-8 mo, 10-12 mo. Serum levels of antinuclear antibody (ANA) and cytokines were determined by ELISA and Luminex, respectively. The cellular composition and function of immune cells in spleen and kidney tissues were characterized by flow cytometry. Urine protein level and pathology were used to evaluate renal damage.
Results: Sle1.lprhomo mice exhibited prominent splenomegaly and lymphadenopathy, associated with early mortality (median lifespan = 4 mo). In contrast, sle1.lprhet mice exhibited a lifespan comparable to sle1 mice (100% alive at 12 mo age), with no evidence of splenomegaly or lymphadenopathy till 12 mo of age. Compared to the sle1 and lpr controls, sle1.lprhet mice exhibited significantly elevated serum IgG anti-dsDNA antibodies, from 4 mo of age (p< 0.05), with the phenotype being more prominent in females. Similar to the serological differences, sle1.lprhet mice exhibited increased proteinuria compared to the single gene controls. Renal pathology assessment is in progress.
To elucidate the mechanistic basis for the observed differences, further cellular, and serological phenotyping was carried out. The percentages of immune subsets including CD4/CD8 T cells, B cells, monocytes, and NK cells in spleens from sle1.lprhet mice at 4-8 mo were comparable with those in the single gene controls. However, when cultured ex-vivo, sle1.lprhet T-cells had an increased propensity to differentiate into both Th1 and Th2 cells, compared to the single gene controls. In contrast, homozygous mutation of FASlpr led to reduced T-reg cells, with profound skewing to effector/memory T-cells, increased CD4:CD8 ratios, and Ki67+ proliferating cells, features associated with lymphoproliferative disease. Indeed homozygous absence of FAS was necessary to upregulate 24 out of 36 serum cytokines interrogated. In contrast, gene dose effects of FASlpr were noted in upregulating serum IL-1 alpha, IL-2 and IL-27.
Conclusion: In contrast to sle1.lprhomo mice which exhibit profound lymphoproliferation and early mortality, sle1.lprhet mice is a more faithful model of human SLE based on its serological and renal phenotypes, without the confounding effect of lymphoproliferation. Whereas the complete absence of FAS leads to impaired activation induced cell death, reduced levels of FAS may regulate T-cell differentiation and production of key cytokines implicated in autoimmunity, including IL-1 alpha, IL-2 and IL-27.
To cite this abstract in AMA style:Bohat R, Xu C, Liang X, Chen Y, Zheng N, Jaffery R, Guerrero A, Egan N, Hicks J, mohan C, Peng W. FASlpr Gene Dosage Differentiates Lymphoproliferative from Non-lymphoproliferative Autoimmunity – a Novel Mouse Model of Lupus [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/faslpr-gene-dosage-differentiates-lymphoproliferative-from-non-lymphoproliferative-autoimmunity-a-novel-mouse-model-of-lupus/. Accessed December 1, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/faslpr-gene-dosage-differentiates-lymphoproliferative-from-non-lymphoproliferative-autoimmunity-a-novel-mouse-model-of-lupus/