Progress in epigenetics on autoimmune rheumatic diseases: from basic studies to bedside in Lupus Erythematosus, Systemic

Abstract

Systemic lupus erythematosus (SLE) is a complex immune dysregulation and its underlying pathoetiology involves multifactorial interaction among various genetic and epigenetic factors. Epigenetic mechanisms can mediate individuals' immune responses to genetic predisposition as well as to several external and internal changing conditions. Alteration in the epigenetic patterns has been proposed as an important contributing factor for the development of autoimmunity, specific phenotypic manifestations and response to treatment. It is known that the obesity epidemic has affected nearly every area of health, including the management of patients with SLE but studies in epigenetics modifications in these diseases are scarce. We hypothesize that the long-term consequences of SLE alone have major impact, but in synergy with excess of adipose tissue, the burden is probably even greater and may be minimized by epigenetic modulation. The primary aim of present proposal is to conduct a series of studies intended to address key knowledge gaps in this topic area, thus facilitating the development of evidence-based and targeted interventions for obesity and SLE patients. Importantly, this research program also aims to create a broad line of research denominated "Nutritional Epigenetic in Rheumatic Diseases". Thus, the main question of this proposal is if there is an epigenetic signature related to lupus and obesity phenotype. More specifically we propose to investigate in this disease the role of obesity in DNA methylation pattern and if this profile is associated with disease manifestations, and whether nutritional treatments, particularly methyl-donors nutrients, can epigenetically modulate the epigenome. For this, the present proposal comprising five studies whose general goal is to extensively investigate this field of research, encompassing a systematic review, in vivo, in vitro and human studies, is characterized by its translational approach. Study 1 aims to perform a systematic review to assess the weight loss management of obese patients with SLE and also identify and describe different types of interventions included in the selected studies. Study 2 has an exploratory concept that aims to explore if there is a specific and different epigenetic profile in obese and normal weight SLE patients, and form the basis of more conclusive researches, especially for those focusing on specific molecular mechanisms. Study 3 consist in a in vivo study which will investigate if a specific immune pathway is epigenetically altered in animal model of SLE under standard and high fat diet and investigate if methyl-donors supplementation reverses or minimizes these possible abnormalities in obese and non-obese animals. Notably, this study will create a new SLE animal's colony and promote its expansion, which is a novel for the university, bring benefits for future studies. Study 4 aims to evaluated a direct and mechanistic link between folic acid treatment, epigenetic patterns and inflammation in adipose tissue cells. This study will bring a novelty: the use of medium secreted from adipose tissue from SLE patients for the cultivation of adipocyte cells, which will allow greater representativeness of the lupus' environment by using secreted factors from human adipose tissue. For last, Study 5 aims to evaluated if folic acid supplementation and vitamin B12 is capable to modulate epigenetic changes in blood and adipose tissue of obese and normal weight SLE patients. Collectively, this ambitious and comprehensive proposal will provide novel insights into the complex relationship between SLE and obesity. Advances in precision medicine/nutrition will be important for the treatment of SLE patients, especially those with obesity, which characterizes the proposal as innovative. Also, it is a proposal with basic to bedside approach, that in addition to its numerous molecular studies, its will provide new insights to therapeutic and clinical applications. (AU)