In examining reasons for premature atherosclerosis in systemic lupus erythematosus (SLE), we previously reported low levels of the cholesterol transport protein apolipoprotein A1 (apoA1) in these patients, and specific antibodies to purified apoA1 were identified in the sera of 5 out of 30 lupus patients. The current study was initiated to determine whether these antibodies are common in lupus patients. 520 serum samples from 175 patients with SLE or primary antiphospholipid syndrome (PAPS) were tested for antibodies to purified apoA1. Positive sera were retested for binding to apolipoprotein incorporated into reconstructed nascent or mature high-density lipoprotein (HDL). Autoantibodies to apoA1 were found in 32.5% of patients with SLE and 22.9% of patients with PAPS, associated with the presence of aPL (anti-beta2 glycoprotein-1, anti-beta2 GP1) antibodies. When reconstructed, nascent and mature HDL molecules were compared as antigen-containing environments, positive sera reacted best to apoA1 embedded in mature HDL molecules. This report confirms the high prevalence of antibodies to apoA1 in patients with systemic lupus and suggests a high affinity of these antibodies for mature HDL.
The heterogenous immunoglobulins known as antiphospholipid antibodies (APLA) or lupus "anticoagulants" (LA) are prevalent in lupus patients and have been implicated in life-threatening thromboembolic events. Unfortunately, observing the presence of these antibodies in an individual does not predict the likelihood of an event nor does it predict when it may occur. A pathogenic role for these antibodies is supported by the observation that high titers and IgG isotype confer an increased risk of thromboembolism. Additionally, numerous reports indicate that isolated patient antibodies interfere with various elements of the coagulation cascade. Nevertheless, attempts to correlate specific antibody characteristics with the future likelihood of a hypercoagulable event in an individual patient have been unsuccessful to date. Given such uncertainty combined with the potential complications of anticoagulant medications, patients are generally not treated until significant morbidity has occurred. Finally, because of the apparent high rate of reoccurrence most patients must remain on anticoagulant therapy indefinitely, regardless of need.
Using lectin blots in conjunction with peptide mapping, α2‐macroglobulin micropurified from systemic lupus erythematosus (SLE) patients was shown to become abnormally glycosylated suggesting the occurrence of complex glycosylation in this pathological condition. To confirm there is indeed a quantitative increase in specific monosaccharides in this protein; α2‐macroglobulin was micropurified from a battery of 37 serum samples which included 6 normal donors (3 male and 3 female), 23 SLE patients, 6 rheumatoid arthritis patients, 1 mixed connective tissue disease patient, and 1 Sjogren's syndrome patient; for carbohydrate analysis. It was noted that the concentration of total monosaccharides in α2‐macroglobulin micropurified from serum samples of SLE patients is significantly higher than normal donors with a mean±SD of 188±410 μg/mg protein (SLE, n=23) versus 14.5±4 μg/mg protein (normal, n=6) even though there was a high variation in the level of monosaccharides among the SLE patients. An increase in oligosaccharides in α2‐macroglobulin from SLE patients compared to normal subjects was confirmed by concanavalin A (Con A) blots using peptide fragments derived from the micropurified protein. Since the interaction of peptide fragments derived from α2‐macroglobulin with Con A requires the presence of mannose and/or glucose residues, we have also examined if there are any correlations between the levels of mannose and glucose in α2‐macroglobulin and SLE. The concentration of mannose (38±60 μg/mg protein) in α2‐macroglobulin derived from SLE patients was significantly higher than normal donors (mannose, 4.8±1 μg/mg protein) however, the concentration of glucose in α2‐macroglobulin derived from SLE patients when compared to normal donors was not statistically significant, 18±20 μg/mg protein in SLE versus 2±0.5 μg/mg protein in normal donors due to high variation between samples. Also, the concentration of galactose in α2‐macroglobulin from SLE patients was significantly higher than normal donors (45.7±173 μg/mg protein versus 0.13±0.03 μg/mg protein). These results illustrate quantification of carbohydrate in selected glycoproteins such as α2‐macroglobulin may be a novel and alternative clinical marker for SLE.
Sex hormone binding globulin (SHBG) is a transport protein in human plasma which regulates the bioavailability of sex hormones, mediates membrane receptor signaling and may affect inflammatory processes, suggesting a regulatory role for this protein in the prevention of atherosclerosis. The current report summarizes literature implicating several members of the SHBG family in the regulation of hormonal and inflammatory processes which may be pertinent to the accelerated atherosclerosis seen in systemic lupus.
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