RICERCA ITALIANA     

Adipokines, inflammatory cytokines and regulatory T cells role in accelerated atherosclerosis and metabolic syndrome pathogenesis, over the course of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune, multisystemic disorder, characterized by a broad spectrum of clinical and immunological manifestations. Many studies have been shown the SLE patients to have a 5 to 10-fold increased risk for cardio-vascular diseases (CVD) compared with age-matched general population, and strikingly this tendency towards CVD is higher for young fertile women. It is now well established that atherosclerosis is characterized by a persistent low-grade inflammatory state. Indeed, immune cell activation is involved in all stages of atherogenesis.
Recently, there is an increasing interest to the role of metabolic syndrome in SLE. Metabolic syndrome is characterized by insulin-resistance (IR), obesity, dyslipidaemia and hypertension and represents an independent cardiovascular and death risk factor from all cause. As in atherogenesis, inflammation plays a crucial role in development and maintenance of insulin resistance, thereby leading to metabolic syndrome.
In the immunoflogistic setting of SLE, the pathogenesis of atherosclerosis and metabolic syndrome may be based on a common inflammatory cellular and molecular milieu, involving proinflammatory cytokines, adipokines and regulatory T cells.
Adipokines leptin, resistin, visfatin and adiponectin, recently discovered peptides secreted by adipose tissue and immune cells, are involved in atherogenesis, metabolic syndrome pathogenesis and inflammation. Many reports suggest an >>>

Principal Investigator

Antonella Maria Vittoria Afeltra Università "Campus Bio-Medico" ROMA

Research Objectives

GENERAL OBJECTIVE.
The aim of the project is to evaluate the cellular and molecular network that underlines the condition of subclinical atherosclerosis and metabolic syndrome, over the course of systemic lupus erythematosus (SLE).

SPECIFIC OBJECTIVES.
Particular attention will be lent to evaluate in SLE patients:
- the adipokines and inflammatory cytokines serum levels, compared to healthy subjects, and their correlation with disease activity scores, metabolic syndrome presence and the endothelial dysfunction and/or damage condition;
- the peripheral blood regulatory T cell Foxp3+ amount and their potential correlation with disease activity scores and the endothelial dysfunction and/or damage grade;
- the possible correlation between adipokines and inflammatory cytokines serum levels and the peripheral blood regulatory T cell Foxp3+ amount, assessing their role in the pathogenesis of SLE;
- the metabolic syndrome prevalence and the potential correlation between any parameter of the syndrome and the disease activity scores and/or inflammation serological markers;
- the presence of endothelial dysfunction and/or damage grade and its possible correlation with the disease activity scores.

First Results

Several epidemiological studies have shown, during the last years, an increased prevalence and a premature onset of cardiovascular disease (CVD), due to atherosclerotic lesions, in patients affected by systemic lupus erythematosus (SLE). Nowadays, CVD represents the main cause of morbidity and mortality among SLE patients. Indeed, many researchers suggested that, in addition to traditional cardiovascular risk factors, over the course of SLE others conditions could be implied in the atherosclerosis (ATS) process: autoantibodies, immunocomplexes, proinflammatory cytokines, oxidative stress, endothelial apoptosis, and steroidal and immunosuppressive treatment.
The ultrasonographic (US) study for intima-media thickness (IMT) determination has been demonstrated to be an effective diagnostic tool for estimation of future cerebral-cardiovascular events onset.
Moreover, echographic parameters of vascular stiffness and the flow-mediated vasodilation (VMD), allow to investigate the presence and severity of endothelial dysfunction, considered the early stage of ATS process. In the light of these evidences, we believe that our project will show an higher endothelial dysfunction and damage degree in SLE patients compared to healthy subjects. This datum may confirm the practical utility of US evaluation also in SLE patients. Thus, the matched US indices of damage and endothelial dysfunction assessment may be suggested as ATS screening tool in lupic population, allowing an >>>

Timescale

24 months

National and international background

Systemic lupus erythematosus (SLE) is an autoimmune, multisystemic disorder, characterized by a broad spectrum of clinical and immunological manifestations. Many studies have been shown the SLE patients to have a 5 to 10-fold increased risk for cardio-vascular diseases (CVD) compared with age-matched general population, and strikingly this propensity towards CVD is higher for young fertile women. Traditional risk factors for atherosclerosis (sex, age, smoke, hypertension, diabetes, dyslipidaemia, obesity, thrombophilic status), alone, doesn’t explain this phenomenon. Pathogenetic events occuring in SLE, such as auto-antibodies production, chronic inflammation, oxidative stress, endothelial apoptosis, renal diseases and treatment-related factors, should be investigated in order to establish their role in atherosclerosis. It is now well established that atherosclerosis is characterized by a persistent low-grade inflammatory state, in which immune cell activation is involved in all stages of atherogenesis. Endothelial dysfunction is defined as the impaired vasorelaxation response to endothelium-dependent vasodilatators such as nitric oxide (NO) or acetylcholine and is also associated with the loss of antithrombotic and anti-inflammatory properties of healthy endothelium. This condition is involved in the early stages of atherogenesis and plays a pivotal role in the initiation and propagation of the atherosclerosis process. Many markers are available to assess the endothelial >>>