Antibodies toward High‐Density Lipoprotein Components Inhibit Paraoxonase Activity in Patients with Systemic Lupus Erythematosus

Abstract

Patients with systemic lupus erythematosus (SLE) have an increased incidence of vascular disease, and oxidative stress is recognized as an important feature in this condition, despite the underlying mechanisms not being fully understood. In these patients, an interaction between lipoproteins and the immune system has been suggested, but most studies have only looked at antibodies against oxidized low-density lipoproteins. This study was undertaken to determine the presence of antibodies directed against high-density lipoproteins (HDL) and to identify a possible association between these antibodies and paraoxonase (PON), an antioxidant enzyme present in HDL. Plasma from 55 patients with SLE was collected and IgG aHDL and antiapolipoprotein A-I (aApo A-I) antibodies were assessed by enzyme-linked immunosorbent assay. Standardization of the method was performed in a control population of 150 healthy subjects. Plasma levels above 5 standard deviations of the mean of the control population were considered positive. PON activity was assessed by quantification of p-nitrophenol formation (micromol/mL/min). Patients with SLE had higher titers of aHDL (P < 0.0001) and aApo A-I (P < 0.0001) antibodies, and lower PON activity (P < 0.0001) than healthy controls. There was also a direct correlation between the titers of aHDL and aApo A-I antibodies (r = 0.61; P < 0.0001). PON activity was inversely correlated with aApo A-I (P = 0.0129) antibody levels. Anti-HDL and aApo A-I antibodies from patients with high titers were isolated and subsequently incubated with human HDL. These antibodies reduced PON activity up to a maximum of 70.2% and 78.4%, respectively. This study showed the presence of aHDL and aApo A-I antibodies in patients with SLE. These antibodies were associated with reduced PON activity in plasma, and the in vitro inhibition assay confirmed a direct inhibition of the enzyme activity.

Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis

“…Paraoxonase is an enzyme associated with high density lipoproteins that may play a role in inflammatory disease (31). Low serum levels of PON1 have been reported in inflammatory disorders (32,33), including rheumatoid arthritis (34), although, in the setting of autoimmunity, most attention as been on the anti-inflammatory effects of PON1 in risk for cardiovascular disease (35). Genetic regulation of Paraoxonase 1 levels has been documented (36,37), although not always by polymorphisms within PON1 (38).…”

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…In fact, this correlation can be explained by the involvement of anti-ApoA1 antibodies in the impairment of HDL function. 96,97 Similarly, in experimental murine lupus model, elevated titers of ApoA1 antibodies were shown to correlate with reduced PON-1 activity and decreased HDL cholesterol concentrations. 98 This in turn reflects the pathological role of ApoA1 IgG in atherosclerosis by disrupting anti-inflammatory and antioxidant properties of HDL mediated by PON-1, an HDL-associated esterase (Figure 1c).…”

Oxidative Stress in Human Autoimmune Joint Diseases

“…On the other hand, SLEDAI score correlates negatively with serum antioxidant enzymes as SOD, and glutathione peroxidase (GPx) (Taysi et al, 2002 b). Auto-antibodies against plasma lipoproteins have been reported in SLE patients (Batuca et al, 2007). The study further documented incidence of antibodies toward high density lipoproteins (HDL) in patients with SLE, and identified Apo A-I as a target of oxidative damage.…”