METHYL-RICH DIET SUPPRESSES THE DEVELOPMENT OF LUPUS-LIKE SYMPTOMS IN HUMANIZED MOUSE MODEL OF THE DISEASE

PV112 / #584 Poster Topic: AS12 - Genetics, Epigenetics, Transcriptomics Background/Purpose SLE is a chronic autoimmune disease with complex involvement of organs and systems. A body of evidence confirmed the central role of environmental factors in lupus pathogenesis with special place assigned to the dietary components. Although a genetic predisposition is required for the onset of SLE, epigenetic factors also play a central role in this process. Having in mind that methyl-containing nutrients are key participants in the DNA methylation processes, and that lupus patients’ DNA shows alterations in this major epigenetic modification, it is intriguing to study the therapeutic effect of these components on SLE progression and clinical manifestations. In the present study we report that the methyl-supplemented diet ameliorates the development of SLE in NSG/Rag2-γc-mice humanized with lupus patients’ PBMCs. Methods Тwo types of rodent diet were used: normal (standard) rodent diet and supplemented diet containing the following ingredients for 8 g of daily portion per mouse (Table 1). Table 1. Amounts of the components (mg/8g diet) in the normal diet and in the high-dose methyl diet. PBMCs from each SLE patient were isolated from peripheral blood. After PBMCs separation, 10 weeks old mice were injected i.p . with 1 billion cells/mouse (2 mice per patient). Two groups of female NSG/Rag2- γ c-mice were engrafted with PBMCs from SLE patients. One group was put on a normal rodent diet, the other – on methyl-supplemented diet. Two groups of control non-humanized mice were also put on either of the diets. The animals were monitored for 8 weeks with blood and urine samples being collected once a week. At the end of the dietary course the mice were sacrificed, and kidneys were examined for glomerular pathology. Assays for appearance of anti-dsDNA antibodies and proteinuria were performed. Results The results showed a decrease in anti-dsDNA antibody and proteinuria levels in the mice put on the supplemented diet, compared to the mice put on normal diet. In addition, histopathological changes in the structure of the glomeruli were observed in the kidney of mice fed with the normal diet but not the supplemented group. The results showed statistically insignificant decrease in the percent atrophic glomeruli of humanized mice put on normal diet (ND group) and of humanized mice put on supplemented diet (SD group). However, the percentages of glomeruli with mesangial proliferation were significantly decreased in mice humanized with PBMCs from patients and put on supplemented diet compared to the humanized mice fed with control diet. Kidney analysis of mice engrafted with lupus patients’ PBMCs and put on normal diet showed moderate mesangial proliferation. On the contrary, mice put on supplemented diet displayed only mild cellular proliferation in the glomeruli. Kidney preparations from non-humanized mice put on normal diet or on supplemented diet did not significantly differ. Conclusions The observed beneficial effect of the methyl-rich diet may be related to the potential modulation of DNA methylation levels and subsequent changes in gene expression. These results point to the importance of DNA methylation as one of the major epigenetic factors responsible for the progression of SLE.

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