Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation and the production of autoantibodies, leading to systemic multiorgan damage. SLE has been reported with diverse prevalence and clinical phenotypes of varying severity, which may be caused by sex hormones, genetic and epigenetic factors, and gut microbiota. Our recent studies showed that a high-fat diet (HFD) exacerbated lupus development and autoimmunity in MRL/lpr lupus-prone mice. Using this model, we investigated the gender bias in autoimmune progression and their systemic response to HFD.

Methods: Twenty male and twenty female MRL/lpr mice were evenly grouped and fed with a regular diet (RD, 10% fat-derived calories) or HFD (60% fat-derived calories). Their body weights were recorded weekly. SLE progression was monitored weekly by skin lesions, urine protein, IgG level, and titers of anti-dsDNA antibody (Ab) and anti-nuclear antibody (ANA) in serum. At week 14 the mice were euthanized. Their spleens were measured and weighed. Kidney and skin from the dorsum of the neck were fixed and embedded for H&E, PAS, and Masson’s staining for histopathological lupus lesions and quantified using kidney index and skin score.

Results: HFD induced a greater weight gain than RD. Additionally, the female group experienced more weight gain than the male group (p< 0.01). SLE skin rash showed up as early as week 6 in both male and female HFD groups. The female HFD group had a greater increase in histopathological skin score than the female RD group (p< 0.01), whereas there was no difference in respective male groups. Splenomegaly and proteinuria were only observed in male HFD mice. Although both males and females had higher serum IgG in the HFD group than the RD group, only the male HFD group showed an increased trend in anti-dsDNA Ab and ANA titers. Kidney pathological changes in the HFD group were more severe in male mice than in female mice, detected by significant increases of kidney index (p< 0.05) and glomerular cell proliferation (p< 0.05).

Conclusion: There is a significant difference of autoimmune progression in male compared to female lupus-prone mice in response to a high fat diet. Our results parallel many known clinical lupus phenotypes and sexual dimorphism in which male patients are more likely to have severe disease (such as nephritis) than female lupus patients, who may have a broader range of lupus symptoms. Elucidation of the cellular and molecular basis of the sex differences in response to a high fat diet in SLE may lead to personalized therapeutic treatment for lupus patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sex-differences-in-autoimmune-pathogenesis-and-systemic-response-to-high-fat-diet-in-lupus-prone-mice/