Session Title: Systemic Lupus Erythematosus – Animal Models Poster
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is characterized by the production of autoantibodies against nuclear antigens (ANA) and phospholipids (aPL). ANA and aPL production have been found to dependent on activation of complex 1 of the mechanistic target of rapamycin (mTORC1) in several mouse models of SLE (Arthritis Rheumatol. 68:2728-2739, 2016). Mouse models of SLE have been indispensable tools for studying disease pathogenesis, however, each model only recapitulates limited aspects of lupus. SLE1.2.3. mice are mice homozygous for three NZM2410-derive lupus susceptibility loci on the C57Bl/6J background. These mice develop systemic autoimmunity with fatal glomerulonephritis and die typically by 12 months of age. Within the last decade, metabolic pathways have been found to regulate lineage specification in the immune system, many of which have been implicated in disease. Here, we investigated immunometabolic checkpoints of disease pathogenesis in SLE1.2.3 mice.
SLE1.2.3 mice have been compared to C57Bl/6 wild-type (WT) controls. Mice were matched for age and gender. Splenic tissue were harvested at 30 weeks of age and examined for lineage specification and metabolic changes within the adaptive and innate arms of the immune system via flow cytometry. ANA and aPL were measured as earlier described (Arthritis Rheumatol. 68:2728-2739, 2016). 10,764 immunometabolic parameters were analyzed by flow cytometry and a p-value of less than 0.05 was considered significant for hypothesis testing.
Male and female WT mice produced 0.520 (±0.042) and 0.670 (±0.057) ug of protein per uL of urine. In contrast, SLE mice had significantly more proteinuria with males and females producing 1.183 (±0.041, p=0.000274) and 0.906 (±0.039, p=0.0279) ug protein per uL urine. There was also significant elevation of autoantibody production with increases in ANA or anti-cardiolipin by as much as 55-fold.
Analysis of the immune system revealed an 18% decrease of CD4+ cells (p=0.02045). Correspondingly, there was a 22% and 34% increase in CD8+ (p=0.02782) and CD4–CD8– double negative (DN) T cells (p=0.01505), respectively. We further found, in male mice, a 31% decrease in CD4+Foxp3+ Tregs and that mTORC1 activity was decreased by 51% and 39% in regulatory subsets such as CD4+Helios+ and CD4+CD25+Helios+ Tregs (p=0.03841, p=0.00631), respectively. In the female mice, mTORC1 activity was decreased in CD4+CD152+ Tregs decreased by 56% (p=0.004407) and mTORC2 activity in CD4+CD25+ Tregs was decreased by 65% (p=0.037331). CD4+CD25+FoxP3+ Tregs were similar in WT and SLE1.2.3 mice.
SLE1.2.3. mice recapitulated lupus pathogenesis which involves ANA and aPL production and glomerulonephritis. Autoantibody production and nephritis has been responsive to mTORC1 blockade with rapamycin. The data suggest that ANA and aPL production may be controlled by mTORC1-dependent development of thymus-derived CD4+CD25+Helios+ Tregs which may serve as targets for therapeutic interventions in SLE.
To cite this abstract in AMA style:Huang N, Lai ZW, Choudhary G, Winans T, Kelly R, Banki K, Morel L, Perl A. Lupus-Prone SLE1.2.3. Mice Exhibit Loss of Thymus-Derived CD4+CD25+Helios+ Tregs [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/lupus-prone-sle1-2-3-mice-exhibit-loss-of-thymus-derived-cd4cd25helios-tregs/. Accessed April 8, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lupus-prone-sle1-2-3-mice-exhibit-loss-of-thymus-derived-cd4cd25helios-tregs/