Background/Purpose: Systematic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease characterized by circulating antinuclear autoantibodies and dysfunction of B cells, T cells, and dendritic cells. Polymorphism of the HRES-1/RAB4 genomic locus has been associated with disease manifestations, such as nephritis, in SLE patients (Arthritis Rheum. 58:532-520), and its Rab4A gene product is overexpressed in T cells of SLE patients and in mice prior to disease onset and, remarkably, inhibition of Rab geranylgeranyl transferase prevented antinuclear antibody (ANA) production and nephritis in lupus-prone mice (Ann. Rheum. Dis. 73:1887-1897). To determine the role of Rab4a in lupus pathogenesis, its impact on ANA production and nephritis was investigated in Rab4A-KO^CD4Cre (Rab4A^KO) mice lacking expression of Rab4A in T cells relative to wild-type (WT) and floxed Rab4A^Q72L knock-in (Rab4A^Q72L) controls.

Methods: Four WT, three Rab4A^Q72L and four Rab4A^KO female mice matched for age were injected intraperitoneally with 0.5 ml per 20 g of body weight of pristane. 14 days after injection, ANA levels were measured in sera by ELISA and immunoglobulin G (IgG) and M (IgM) and complement 3 (C3) deposition as well as infiltration by CD11b⁺ macrophages, CD11c⁺ dendritic cells, CD138⁺ plasma cells, and CD3⁺ T cells were assessed by immunofluorescence using confocal microscopy. Statistical analyses were performed by t-test; two-tailed p<0.05 was considered significant.

Results: ANA levels were increased in Rab4A^KO relative to Rab4A^Q72L controls. Deposition of IgG and IgM was increased 2-fold, and C3 deposition was increased 4-fold in glomeruli of Rab4A^KO relative to WT and Rab4A^Q72L controls. Further, T cells (12-fold), plasma cells (2-fold), and macrophages (7-fold), but not dendritic cels, were accumulated in glomeruli and tubular interstitium of Rab4A^KO mice relative to WT and Rab4A^Q72L controls.

Conclusion: Based on these results, Rab4A protects against ANA production and nephritis in the pristane-induced model of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rab4a-protects-from-antinuclear-antibody-production-and-nephritis-in-the-pristane-induced-model-of-sle/