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In mice vaccination with Streptococcus pneumoniae results in an increase in anti-oxLDL IgM antibodies due to mimicry of anti-phosphorylcholine (present in the cell wall of S. pneumoniae) and anti-oxLDL IgM. In this study we investigated the human translation of this molecular mimicry by vaccination against S. pneumoniae using the Prevenar-13 vaccine. Twenty-four healthy male volunteers were vaccinated with Prevenar-13, either three times, twice or once in a double-blind, placebo-controlled, randomized single center clinical study. Anti-pneumococcal wall, oxLDL and phosphorycholine antibody levels were measured at a fixed serum dilution, as well as circulating lipid levels over the course of 68 weeks. A significant increase in anti-oxLDL IgG and IgM was seen in the group receiving two doses six months apart compared to the placebo. However, these differences were not observed in the groups receiving a single dose, two doses one month apart, or three doses. This study shows that vaccination with Prevenar-13 does not result in robust anti-oxLDL IgM levels in humans. Further research would be required to test alternative pneumococcal-based vaccines, vaccination regimens or study populations, such as cardiovascular disease patients.

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide 1 . The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) 2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall 2 . A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs 3 , but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis. The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.

Neutrophil extracellular traps (NETs) are DNA–protein structures released by neutrophils in response to various stimuli, including oxidized, low-density lipoprotein (oxLDL). Accumulating evidence suggests a role for NETs in the pathogenesis of abdominal aortic aneurysm (AAA). In this study, we investigated the potential association of lipoprotein particles and NETs in AAA in comparison to non-AAA control groups. The concentrations of neutrophil myeloperoxidase (MPO), the NET parameters citrullinated histone H3 (citH3) and circulating cell-free DNA (cfDNA), as well as of blood lipids were determined in plasma or serum of patients with AAA (n = 40), peripheral artery occlusive disease (PAD; n = 40) and healthy donors (n = 29). A sandwich ELISA detecting oxidized phosphatidylcholine in association with apolipoprotein B-100 (oxPL/apoB) was applied to measure oxidized phospholipids in circulation. The effect of lipoparticles on NET formation was tested using a DNA release assay with isolated human neutrophils. Plasma MPO, citH3 and cfDNA levels were significantly increased in AAA patients in comparison to healthy donors and PAD patients. Plasma concentrations of citH3 positively correlated with serum oxPL/apoB in AAA patients. In functional in vitro assays, the addition of oxLDL induced NET formation in pre-stimulated neutrophils. In conclusion, our data suggest a promoting role of oxLDL on NET formation in AAA patients.

Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications—myocardial infarction and stroke—are the leading cause of mortality worldwide 1,2 . Recent studies have identified triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions 3 , to be highly expressed in macrophage foam cells in experimental and human atherosclerosis 4 . However, the role of TREM2 in atherosclerosis is not fully known. Here we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased, necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis.

BackgroundSerological tests are widely used in various medical disciplines for diagnostic and monitoring purposes. Unfortunately, the sensitivity and specificity of test systems are often poor, leaving room for false-positive and false-negative results. However, conventional methods were used to increase specificity and decrease sensitivity and vice versa. Using SARS-CoV-2 serology as an example, we propose here a novel testing strategy: the ‘sensitivity improved two-test’ or ‘SIT²’ algorithm.MethodsSIT² involves confirmatory retesting of samples with results falling in a predefined retesting zone of an initial screening test, with adjusted cut-offs to increase sensitivity. We verified and compared the performance of SIT² to single tests and orthogonal testing (OTA) in an Austrian cohort (1117 negative, 64 post-COVID-positive samples) and validated the algorithm in an independent British cohort (976 negatives and 536 positives).ResultsThe specificity of SIT² was superior to single tests and non-inferior to OTA. The sensitivity was maintained or even improved using SIT² when compared with single tests or OTA. SIT² allowed correct identification of infected individuals even when a live virus neutralisation assay could not detect antibodies. Compared with single testing or OTA, SIT² significantly reduced total test errors to 0.46% (0.24–0.65) or 1.60% (0.94–2.38) at both 5% or 20% seroprevalence.ConclusionFor SARS-CoV-2 serology, SIT² proved to be the best diagnostic choice at both 5% and 20% seroprevalence in all tested scenarios. It is an easy to apply algorithm and can potentially be helpful for the serology of other infectious diseases.

Background Lipid oxidation of membrane phospholipids is accompanied by the formation of oxidation-specific epitopes (OSE). These epitopes are recognized by specific antibodies and represent danger-associated molecular patterns that are generated during chronic inflammatory processes. In a murine model for hepatic inflammation during non-alcoholic fatty liver disease (NAFLD), increased antibody levels targeting OSE were found to be protective. Here, our aim was to determine an association between OSE-specific antibody titers and NAFLD in humans. Methods IgM and IgG levels with specificity for various OSE were assessed in the plasma of patients with NAFLD ( n =  71) and healthy controls ( n =  68). Antibody titers were comprehensively analyzed in patients with NAFLD after classification by histological evaluation of liver biopsies. Statistical analysis was performed to determine significant correlations and odds ratios. To study the specificity for NAFLD, plasma antibody titers were measured in patients with hepatitis C ( n  = 40) and inflammatory bowel disease ( n =  62). Results IgM titers against OSE were lower in patients with NAFLD compared to controls. Further biopsy-based classification of patients with NAFLD did not show any difference in IgM levels. Plasma IgM titers towards the P1 mimotope demonstrated an inverse correlation with markers for obesity, systemic inflammation, and liver damage. In contrast, hepatitis C and increased disease activity during inflammatory bowel disease was not associated with reduced IgM titers. Conclusions Our data highlight the importance of immune recognition of OSE by IgM antibodies in the pathophysiology of NAFLD.

Summary Pancreatic cancer is a very aggressive malignant disease due to lack of early diagnosis and chemotherapeutic resistance of the tumor cells. There is distinct evidence that food derived polyphenols possess chemopreventive effects in the development of several cancers including pancreatic carcinoma. Resveratrol is one of those phenolic compounds found in grape skins and other fruits with known anticancer activity. Various polymethoxylated resveratrol derivatives showed stronger antiproliferative effects than resveratrol in tumor cell lines. The aim of our study was to evaluate the cytotoxic and biochemical effects of a newly synthesized polymethoxylated resveratrol analogue, N -hydroxy- N ′-(3,4,5-trimethoxphenyl)-3,4,5-trimethoxy-benzamidine (KITC) in two human pancreatic cancer cell lines. The human pancreatic cancer cell lines, AsPC-1 and BxPC-3 were used to test the potential inhibitory effect of the resveratrol derivative on cell proliferation and the underlying mechanisms of this effect. After 7 days of incubation, KITC inhibited the growth of AsPC-1 and BxPC-3 cells with IC 50 values of 9.6 and 8.7 μM, respectively. KITC (40 μM) arrested cells in the G0/G1 phase and depleted cells in the S phase of the cell cycle (−105% and −35% of control, respectively). KITC induced dose-dependent apoptosis in both pancreatic cancer cell lines and was found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of DNA synthesis. Employing growth inhibition assays, KITC acted synergistically with gemcitabine in both cell lines. In summary, we found that KITC exerted considerable antitumor activity against human pancreatic cancer cells and could be a promising candidate for further investigations to establish a new chemotherapeutic regimen.

The inhibitory immunoreceptor SIRPα is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRPα on B1 lymphocytes, a non-conventional subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPαΔCYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective we investigated the involvement of SIRPα signaling in atherosclerosis development. Bone marrow (SIRPαΔCYT>LDLR−/−) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRPα as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRPα as a potential therapeutic target in atherosclerosis.

The inhibitory immunoreceptor SIRP? is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRP? on B1 lymphocytes, a non-conventional subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPαΔCYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective we investigated the involvement of SIRPα signaling in atherosclerosis development. Bone marrow (SIRPαΔCYTLDLR-/-) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRPα as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRPα as a potential therapeutic target in atherosclerosis.