IgM-antibodies against phosphorylcholine in mothers and normal or low birth weight term newborn infants.

OBJECTIVE: To determine levels of athero-protective IgM antibodies against phosphorylcholine in mothers and term-born normal or low birth weight infants. APPROACH: Twenty three mother-infant pairs were studied, of whom 16 infants were within the normal weight range for gestational age (NGA; 3652[504] g) and 7 were small for gestational age (SGA; birth weight: 2715[255] g), the latter <2SD below the Swedish reference data mean for normal fetal growth. All infants were born at term (mean ± SD 40.5 ± 1.1 weeks). Serum was available from 6 mothers with SGA and 14 with NGA infants. Participating mothers were aged 34.0 ± 3.9 years (no difference between groups). Fourteen neonates were boys and seven were girls. Levels of anti-PC IgM were determined by ELISA. RESULTS: Neonatal IgM anti-PC levels were low (undetectable in 8 infants out of which 3 were SGA) with a median of 76[range 0-2.51] U/ml. Maternal IgM anti-PC levels were significantly higher (median 7198[range: 25.32-656.0]) U/ml) and the proportion of mothers in highest quartile (>75th percentile) was larger in mothers of NGA-infants (43%) vs. those of SGA-infants (0%, p = 0.032). CONCLUSIONS: IgM anti-PC levels are low at birth, which suggests that these antibodies do not play a "housekeeping" role in immune function during fetal life/development, but arise predominately on exposure to external antigens after birth. Furthermore, low maternal IgM anti-PC levels may play a role in placental insufficiency, contributing to poor fetal growth and a small-for-date baby. This preliminary observation may have implications for the future risk of atherosclerosis/cardiovascular disease development in pregnant women and their offspring

Antibodies against native and oxidized cardiolipin and phosphatidylserine and phosphorylcholine in atherosclerosis development.

BACKGROUND: Antibodies against cardiolipin and phosphatidylserine (anti-CL and anti-PS) are associated with thrombosis. In contrast, we determined that IgM antibodies against oxidized CL and PS (OxCL and OxPS) and phosphorylcholine (anti-PC) could be protection markers for cardiovascular disease (CVD). METHODS: 226 individuals with established hypertension (diastolic pressure>95 mmHg) from the European Lacidipine Study on Atherosclerosis. Antibodies were tested by ELISA. As a surrogate measure of atherosclerosis, the mean of the maximum intima-media thicknesses (IMT) in the far walls of common carotids and bifurcations was determined by ultrasonography at the time of inclusion and 4 years following inclusion. RESULTS: Increases in IMT measures at follow-up were significantly less common in subjects which at baseline had high IgM anti-OxPS and anti-PC at above 75th percentile: OR 0,45, CI (0,23-0,86) and OR 0.37, CI (0,19-0,71), p = 0.0137 respectively and above 90th percentile: OR 0.32, CI (0,12-0,84) and OR 0.39, CI (0,15-1.00), p = 0.050 and OR 0,22, CI (0,08-0,59) p = 0,0029. IgM anti-OxCL was negatively associated with IMT increases (OR, 0.32, CI (0,12-0,84), p = 0231). There were no associations for IgM anti-PS or anti-CL. Anti-PC, as determined herein by a commercial ELISA, was strongly associated with data from our previously published in house ELISA (R = 0,87; p<0,0001).) Anti-PC was also a risk marker at low levels (below 25th percentile; OR = 2,37 (1,16-4,82), p = 0,0177). CONCLUSIONS: High levels of IgM anti-OxPS and anti-OxCL, but not traditional anti-phospholipid antibodies (anti-PS and anti-CL), are associated with protection against atherosclerosis development. In addition, low IgM anti-PC was a risk marker but high a protection marker

Levels of phosphorylcholine antibodies (IgM anti-PC) among newborn infants with normal (normal for gestational age: NGA, n = 16) or low birth weight (small for gestational age; SGA: birth weight 2 SD or more below the reference mean, n = 7), and in their mothers.

<p>Levels of phosphorylcholine antibodies (IgM anti-PC) among newborn infants with normal (normal for gestational age: NGA, n = 16) or low birth weight (small for gestational age; SGA: birth weight 2 SD or more below the reference mean, n = 7), and in their mothers.</p

Levels of phosphorylcholine antibodies (IgM anti-PC) in newborn infants born at term and in their mothers, stratified by normal (normal for gestational age:NGA, n = 7) or low (small for gestational age:SGA, n = 16)birth weight.

<p>IQR = inter quartile range.</p><p>Levels of phosphorylcholine antibodies (IgM anti-PC) in newborn infants born at term and in their mothers, stratified by normal (normal for gestational age:NGA, n = 7) or low (small for gestational age:SGA, n = 16)birth weight.</p

Induction of Dendritic Cell–Mediated T-Cell Activation by Modified but Not Native Low-Density Lipoprotein in Humans and Inhibition by Annexin A5

International audienceObjective— Atherosclerosis is an inflammatory disease, where activated immunocompetent cells, including dendritic cells (DCs) and T cells are abundant in plaques. Low-density lipoprotein modified either by oxidation (oxLDL) or by human group X-secreted phospholipase A2 (LDLx) and heat shock proteins (HSP), especially HSP60 and 90, have been implicated in atherosclerosis. We previously reported that Annexin A5 inhibits inflammatory effects of phospholipids, decreases vascular inflammation and improves vascular function in apolipoprotein E −/− mice. Here, we focus on the LDLx effects on human DCs and T cells. Approach and Results— Human DCs were differentiated from peripheral blood monocytes, stimulated by oxLDL or LDLx. Naive autologous T cells were cocultured with pretreated DCs. oxLDL and LDLx, in contrast to LDL, induced DC-activation and T-cell proliferation. T cells exposed to LDLx-treated DCs produced interferon-γ, interleukin (IL)-17 but not IL-4 and IL-10. Annexin A5 abrogated LDLx effects on DCs and T cells and increased production of transforming growth factor-β and IL-10. Furthermore, IL-10 producing T cells suppressed primary T-cell activation via soluble IL-10, transforming growth factor-β, and cell–cell contact. Lentiviral-mediated shRNA knock-down HSP60 and 90 in DCs attenuated the effect of LDLx on DCs and subsequent T-cell proliferation. Experiments on DC and T cells derived from carotid atherosclerotic plaques gave similar results. Conclusions— Our data show that modified forms of LDL such as LDLx but not native LDL activate human T cells through DCs. HSP60 and 90 contribute to such T-cell activation. Annexin A5 promotes induction of regulatory T cells and is potentially interesting as a therapeutic agent

Induction of dendritic cell-mediated T-cell activation by modified but not native low-density lipoprotein in humans and inhibition by annexin a5: involvement of heat shock proteins

International audienceObjective— Atherosclerosis is an inflammatory disease, where activated immunocompetent cells, including dendritic cells (DCs) and T cells are abundant in plaques. Low-density lipoprotein modified either by oxidation (oxLDL) or by human group X-secreted phospholipase A2 (LDLx) and heat shock proteins (HSP), especially HSP60 and 90, have been implicated in atherosclerosis. We previously reported that Annexin A5 inhibits inflammatory effects of phospholipids, decreases vascular inflammation and improves vascular function in apolipoprotein E −/− mice. Here, we focus on the LDLx effects on human DCs and T cells. Approach and Results— Human DCs were differentiated from peripheral blood monocytes, stimulated by oxLDL or LDLx. Naive autologous T cells were cocultured with pretreated DCs. oxLDL and LDLx, in contrast to LDL, induced DC-activation and T-cell proliferation. T cells exposed to LDLx-treated DCs produced interferon-γ, interleukin (IL)-17 but not IL-4 and IL-10. Annexin A5 abrogated LDLx effects on DCs and T cells and increased production of transforming growth factor-β and IL-10. Furthermore, IL-10 producing T cells suppressed primary T-cell activation via soluble IL-10, transforming growth factor-β, and cell–cell contact. Lentiviral-mediated shRNA knock-down HSP60 and 90 in DCs attenuated the effect of LDLx on DCs and subsequent T-cell proliferation. Experiments on DC and T cells derived from carotid atherosclerotic plaques gave similar results. Conclusions— Our data show that modified forms of LDL such as LDLx but not native LDL activate human T cells through DCs. HSP60 and 90 contribute to such T-cell activation. Annexin A5 promotes induction of regulatory T cells and is potentially interesting as a therapeutic agent

IgM antibodies to oxidized phosphatidylserine as protection markers in cardiovascular disease among 60-year olds.

OBJECTIVE:Phosphatidylserine is exposed on apoptotic cells and is prone to oxidation (OxPS). Here we analyze the association of IgM antibodies against OxPS (anti-OxPS) with the risk of cardiovascular disease (CVD). METHODS:Among sixty-year olds from Stockholm County in Sweden, previously screened for cardiovascular risk factors (2039 men, 2193 women), there were 210 incident CVD-cases identified during a 5-year follow-up. Using a nested case-control design, 622 age- and sex-matched controls were selected. Odds ratios (OR) with 95% intervals (CI) were calculated by conditional logistic regression. IgM anti-OxPS was measured by ELISA. Phagocytosis of apoptotic Jurkat-cells by macrophages was studied by flow cytometry. RESULTS:Anti-OxPS levels were lower among cases (median (interquartile range): 80.7 (60.9-101.0 vs. 84.6 (65.8-109.6); p = 0.047); among men (76.6 (55.8-99.2) vs. 82.0 (63.1-105.1); p = 0.022) and among women 89.6 (72.3-110.1) vs. 89.8 (69.9-114.4); p = 0.79). After adjustment for smoking, BMI, diabetes mellitus type II, hypercholesterolaemia and hypertension, and dividing into quartiles, using the highest quartile (quartile 4) as reference, quartile 3 was associated with a OR of 1.74 (CI 1.08-2.81). Quartiles 2 and 1 had similar associations, the later reaching statistical significance. Among men associations were stronger whereas no significant associations were observed in women. The OR of MI/angina comparing quartile 3 with quartile 4 was 2.31 (CI 1.30-4.11). The OR for quartile 2 and 1, respectively, were similar as for quartile 3. Total IgM increased uptake of apoptotic cells, which was reversed if incubated with OxPS. CONCLUSIONS:IgM anti-OxPS is a novel potential protection marker for CVD, in particular in men. Increased phagocytosis of dying/dead cells could be one potential underlying mechanism

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ABSTRACT. Objective. We have reported that the prevalence of atherosclerotic plaques and their echolucency was increased in systemic lupus erythematosus (SLE). We here study antibodies against oxidized cardiolipin (anti-OxCL) and phosphatidylserine (anti-OxPS) in SLE and in relation to atherosclerosis measures. Methods. Patients with SLE (n = 114) were compared with age-and sex-matched population-based controls (n = 122). Common carotid intima-media thickness and plaque occurrence were determined by B-mode ultrasonography. Plaques were graded according to echogenicity as 1-4, with 1 being echolucent. Antibodies were determined by ELISA. Results. In the SLE group, the prevalence of low IgM anti-OxPS and low total IgM levels (below 33rd percentile) was increased compared to controls (p = 0.045 and p = 0.0079, respectively). Among SLE patients with atherosclerotic plaques, the prevalence of low IgM anti-OxPS (p = 0.0019) and anti-OxCL (p = 0.031) was increased. Only IgM anti-OxPS remained significant (p = 0.019) after adjusting for other significant factors. Echolucent plaques (total, or left side) were more prevalent among SLE patients with low IgM anti-OxCL and anti-OxPS when controlled for other significant factors (p &lt; 0.05). Low total IgM was independently associated with echolucent plaque on left side (p &lt; 0.05), but not other atherosclerosis measures. IgM anticardiolipin antibodies (aCL) and antiphosphatidylserine antibodies (anti-PS) were higher among SLE patients with cardiopulmonary disease, including arterial, valvular, and venous disease (p &lt; 0.05). There were no associations between antibodies and other disease manifestations or activity. Both anti-OxCL and anti-OxPS, in contrast to aCL, and anti-PS, were cofactor-β 2 -glycoprotein I (β 2 -GPI)-independent. Conclusion. The prevalence of low levels of IgM anti-OxCL and anti-OxPS (both cofactor-β 2 -GPI-independent) is associated with the presence of plaques and echolucent plaques i