Low Levels of Antibodies Against Phosphorylcholine Predict Development of Stroke in a Population-Based Study From Northern Sweden

Abstract

Background and Purpose-Natural immunoglobulin M antibodies specific for phosphorylcholine (anti-PC) have been implicated in atherosclerosis. We have shown previously that high levels of anti-PC predict a slower progression of atherosclerosis in humans and that low levels of anti-PC are associated with higher risk for cardiovascular disease. Here we determine the association between anti-PC and the incidence of stroke. Methods-Using a nested case control study design, we examined 227 incident cases (125 men and 102 women) of first-time stroke and 455 age-and sex-matched controls identified during a 13-year time period (1985 to 1999) within the population-based cohorts of the Västerbotten Intervention Project (VIP) and the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease (WHO MONICA) project in Northern Sweden. Odds ratios of stroke with 95% CIs with adjustments for age, gender, smoking, serum cholesterol, diabetes, body mass index, and blood pressure were determined. Anti-PC levels were measured using ELISA. Results-A significant association between low levels of anti-PC at baseline and incident stroke was seen for the whole group of anti-PC levels below the 30th percentile (multivariately adjusted odds ratio, 1.62; CI, 1.11 to 2.35). Analyses of gender-specific associations indicated fairly strong associations for females, especially at the lowest 30th percentile (multivariately adjusted odds ratio, 2.65; CI, 1.41 to 4.95). No associations were noted for men. Conclusion-Low anti-PC is a novel independent risk marker for development of stroke. Measurements of anti-PC could be used to identify immunodeficient subjects at an increased risk for stroke. The possibility that such subjects might be targets for novel modes of treatment such as immunotherapies deserves further investigation. (Stroke. 2010;41:607-612.)

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

“…Subsequent research has demonstrated that anti-PC aids in clearance of apoptotic cells (6,30) and prevents the formation of pathogenic foam cells in atherosclerosis by clearing oxidized low density lipoprotein (1). Murine studies with PC vaccination have shown strong beneficial effects on experimental atherosclerosis in vivo (11)(12)(13), and human epidemiology has consistently linked anti-PC insufficiency to cardiovascular events (14)(15)(16)(17). These findings in combination with earlier knowledge on the presence of T15 B cells in germ-free mice (20) has led to the formulation of a hypothesis that germlineencoded PC-reactive Abs produced by innate B1 cells fulfill an important housekeeping function in human physiology (8,10).…”

“…Although our data does not preclude the possibility of germline encoded innate anti-PC in humans, it seems clear that in adults, if present, this putative innate response is overshadowed by an adaptive thymus independent-process mediated by conventional B cells. Innate or not, this is still a clinically relevant immune response, and multiple studies have consistently confirmed that having a low titer of anti-PC is an independent risk factor for cardiovascular disease (14)(15)(16)(17).…”

“…These results have lead scientists to hypothesize that anti-PC has an important housekeeping function in homeostasis (8)(9)(10). This understanding has been further cemented by animal studies (11)(12)(13) and several large epidemiological studies (14)(15)(16)(17), which have consistently demonstrated that humans with low levels of anti-PC are at elevated risk of cardiovascular disease. Furthermore, high levels of anti-PC are negatively associated with atherosclerosis development in humans (18).…”

Microbial Modulation of Host Immunity with the Small Molecule Phosphorylcholine

“…As a case in point, anti-ChoP antibodies that bind to dental plaque bacteria cross-react with oxidized low-density lipoprotein (oxLDL), which contains ChoP (104). 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).…”

Rheumatic Diseases

“…15 This association appears to be accentuated in stroke. 16 Furthermore, low levels of IgM anti-PC were associated with SLE in a nested case-control SLE study 17 and in a new SLE case-control study (unpublished); further anti-PC was antiinflammatory, inhibiting the effects of inflammatory phospholipids. 17 Thus, low anti-PC could predispose to both atherosclerosis and rheumatic disease, illustrating 1 possible common underlying factor that deserves further study.…”