Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease with features of autoantibodies, skin rash, kidney and other multiple organ involvement. Evidence shows that obesity is a major factor contributing to the onset and progression of autoimmune diseases including SLE and is highly linked to their cumulative organ damage. Our previous study and others have shown that circulating T follicular helper (Tfh) cells are implicated in promoting B cells production of autoantibodies and shape the composition of the gut microbiota thus modulating obesity.  In this study, we evaluated the impact of high fat diet (HFD) on the development of SLE and obesity, and the pathophysiologic link of obesity, SLE, and Tfh cells in MRL/lpr lupus prone mice.

Methods: Thirty MRL/lpr mice were fed a regular diet (RD, 10% calories from fat) or high fat diet (HFD, 60% calories from fat) beginning at 2 months of age, half male and half female. Their body weights and skin lesions were recorded weekly. Urine protein was assessed weekly by Bradford assay. Blood was collected monthly for serum IgG, anti-dsDNA antibody, and anti-nuclear antibody (ANA) detection. At week 14, mice were euthanized, their spleen were measured and weighed. Kidney and skin biopsy were embedded in paraffin and tissue sections for H&E, PAS, and Masson’s staining to detect lupus histopathological lesions and quantified as kidney index and histological skin score based on glomerular cellularity, glomerular deposits, interstitial inflammation, and inflammatory dermatitis. Tfh cells (CD4⁺CXCR5⁺) were examined in blood and splenic sections by flow cytometry and immunofluorescent staining.

Results: The HFD group induced a significant increase in mouse body weight by week 3 and continued until week 14 compared to RD group (p< 0.05 to p< 0.01). Skin lesions on the dorsum of neck, forehead, and ears in HFD group, resembling human discoid lupus, manifested as earliest as week 6 and occurred in 55.6% of the HFD group vs 11.1% of the RD group (p< 0.05). Splenomegaly was observed in the HFD mice (p< 0.05). Proteinuria was increased from week 11 to week 14 in HFD group. There was an increase trend of anti-dsDNA antibody and serum IgG titer in HFD group, but no difference of ANA was observed between HFD and RD groups. HFD mice also had a higher histological score of skin (p< 0.05) and higher acute and chronic index of kidney than RD mice. Significant increase of CD4⁺CXCR5⁺ Tfh cells was observed in both blood and spleen in HFD group mice.

Conclusion: Our results show that a high fat diet induced an accelerated and more severe form of lupus development and autoimmunity in MRL/lpr mice. This indicates that HFD exacerbates the development of SLE. The elevated disease course in HFD mice was accompanied by increased of Tfh cells. Interventions of healthy diet or targeting Tfh cells may improve both lupus symptoms and outcomes in genetically predisposed SLE patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-fat-diet-as-a-catalyst-to-lupus-development-and-autoimmunity-in-mrl-lpr-mice/