IgM autoantibodies to distinct apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with SLE

Abstract

Emerging evidence suggests that there are IgM-autoantibodies that may play protective roles in SLE. While IgM are often considered polyreactive, we postulate that there are distinct sets of IgM-autoantibodies of defined autoreactive specificities relevant to different features of SLE. We examined the relationships between levels of IgM natural autoantibodies (NAbs) to apoptosis-associated phosphorylcholine (PC) or malondialdehyde (MDA) antigens, with lupus-associated autoantibodies and features of disease, in 120 SLE patients. IgM anti-PC was significantly higher in patients with low disease activity and less organ damage determined by the SELENA-SLEDAI, the physician's evaluation and the SLICC damage score. Furthermore, IgM anti-PC was significantly higher in patients without cardiovascular events. In contrast, IgM anti-cardiolipin and IgM anti-dsDNA were significantly higher in patients without renal disease. These results support the hypothesis that some IgM autoantibodies are part of a natural immune repertoire that provide homeostatic functions and protection from certain clinical lupus features.

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses

“…Indeed, an increase in the production, or an impairment of phagocytic clearance, of ACs is a common component of many chronic inflammatory conditions, including murine models of accelerated atherogenesis in which anti-AC natural antibodies have been implicated in protective responses (42,43). With the current elucidation of a direct anti-inflammatory effect of this type of natural antibody, our studies provide a plausible explanation for the recent finding that high levels of PCspecific IgM in humans correlate with protection from myocardial infarction and stroke in at-risk clinical populations (44,45). In addition, as nucleic acid-containing immune complexes are postulated to contribute to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), our findings that these responses are modulated by anti-AC IgM may explain recent evidence from surveys of SLE patients that higher anti-AC NAb levels correlated with lower disease activity and organ injury (44).…”

“…With the current elucidation of a direct anti-inflammatory effect of this type of natural antibody, our studies provide a plausible explanation for the recent finding that high levels of PCspecific IgM in humans correlate with protection from myocardial infarction and stroke in at-risk clinical populations (44,45). In addition, as nucleic acid-containing immune complexes are postulated to contribute to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), our findings that these responses are modulated by anti-AC IgM may explain recent evidence from surveys of SLE patients that higher anti-AC NAb levels correlated with lower disease activity and organ injury (44). The cellular source of these protective IgM antibodies may have been conserved during immune evolution, as IgM anti-PC antibodies have recently been reported to also be predominantly produced by human B-1 cells (46).…”

Multispecificity of Immunoglobulin M Antibodies Raised against Advanced Glycation End Products

“…In the murine immune system, natural IgM Abs that recognize apoptotic cells have been shown to enhance the phagocytic clearance of dead and dying cells and to suppress innate immune signaling pathways. In patients with SLE, the IgM auto-Abs, which bind to the neo-epitopes on apoptotic cells, have been demonstrated to be present at significantly higher levels in patients with a lower disease activity and with less severe organ damage (38). On the other hand, Witte (39) proposed a possible mechanism of protection by the IgM auto-Abs against the dsDNA, in which the IgM Abs may improve the clearance of pathogenic immune complexes containing IgG.…”

Microbial Modulation of Host Immunity with the Small Molecule Phosphorylcholine

“…Reduced anti-ChoP IgM levels in patients with acute cardiovascular disease correspond with increased risk of a new cardiovascular event (105,106). Also, higher anti-ChoP IgM levels correlate with decreased symptomology for systemic lupus erythematosus (SLE) patients (107). These effects, however, are not limited to anti-ChoP antibodies.…”