324 research outputs found
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Secreted IgM deficiency leads to increased BCR signaling that results in abnormal splenic B cell development.
Mice lacking secreted IgM (sIgM -/-) antibodies display abnormal splenic B cell development, which results in increased marginal zone and decreased follicular B cell numbers. However, the mechanism by which sIgM exhibit this effect is unknown. Here, we demonstrate that B cells in sIgM -/- mice display increased B cell receptor (BCR) signaling as judged by increased levels of phosphorylated Bruton's tyrosine kinase (pBtk), phosphorylated Spleen tyrosine kinase (pSyk), and nuclear receptor Nur77. Low dosage treatment with the pBtk inhibitor Ibrutinib reversed the altered B cell development in the spleen of sIgM -/- mice, suggesting that sIgM regulate splenic B cell differentiation by decreasing BCR signaling. Mechanistically, we show that B cells, which express BCRs specific to hen egg lysozyme (HEL) display diminished responsiveness to HEL stimulation in presence of soluble anti-HEL IgM antibodies. Our data identify sIgM as negative regulators of BCR signaling and suggest that they can act as decoy receptors for self-antigens that are recognized by membrane bound BCRs
Apoptotic Cells with Oxidation-specific Epitopes Are Immunogenic and Proinflammatory
Oxidation of low density lipoprotein (LDL) generates a variety of oxidatively modified lipids and lipid-protein adducts that are immunogenic and proinflammatory, which in turn contribute to atherogenesis. Cells undergoing apoptosis also display oxidized moieties on their surface membranes, as determined by binding of oxidation-specific monoclonal antibodies. In the present paper, we demonstrated by mass spectrometry that in comparison with viable cells, membranes of cells undergoing apoptosis contain increased levels of biologically active oxidized phospholipids (OxPLs). Indeed, immunization of mice with syngeneic apoptotic cells induced high autoantibody titers to various oxidation-specific epitopes of oxidized LDL, including OxPLs containing phosphorylcholine, whereas immunization with viable thymocytes, primary necrotic thymocytes, or phosphate-buffered saline did not. Reciprocally, these antisera specifically bound to apoptotic cells through the recognition of oxidation-specific epitopes. Moreover, splenocyte cultures from mice immunized with apoptotic cells spontaneously released significant levels of T helper cell (Th) 1 and Th2 cytokines, whereas splenocytes from controls yielded only low levels. Finally, we demonstrated that the OxPLs of apoptotic cells activated endothelial cells to induce monocyte adhesion, a proinflammatory response that was abrogated by an antibody specific to oxidized phosphatidylcholine. These results suggest that apoptotic cell death generates oxidatively modified moieties, which can induce autoimmune responses and a local inflammatory response by recruiting monocytes via monocyte–endothelial cell interaction
Lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease:European Atherosclerosis Society/European Society of Vascular Medicine Joint Statement
Patients with peripheral arterial disease (PAD) are at very high risk of cardiovascular events, but risk factor management is usually suboptimal. This Joint Task Force from the European Atherosclerosis Society and the European Society of Vascular Medicine has updated evidence on the management on dyslipidaemia and thrombotic factors in patients with PAD. Guidelines recommend a low-density lipoprotein cholesterol (LDLC) goal of more than 50% reduction from baseline and <1.4 mmol/L (<55 mg/dL) in PAD patients. As demonstrated by randomized controlled trials, lowering LDL-C not only reduces cardiovascular events but also major adverse limb events (MALE), including amputations, of the order of 25%. Addition of ezetimibe or a PCSK9 inhibitor further decreases the risk of cardiovascular events, and PCSK9 inhibition has also been associated with reduction in the risk of MALE by up to 40%. Furthermore, statin- based treatment improved walking performance, including maximum walking distance, and pain-free walking distance and duration. This Task Force recommends strategies for managing statin-associated muscle symptoms to ensure that PAD patients benefit from lipid-lowering therapy. Antiplatelet therapy, either daily clopidogrel 75 mg or the combination of aspirin 100 mg and rivaroxaban (2×2.5 mg) is also indicated to prevent cardiovascular events. Dual pathway inhibition (aspirin and rivaroxaban) may be considered following revascularization, taking into account bleeding risk. This Joint Task Force believes that adherence with these recommendations for lipid-lowering and antithrombotic therapy will improve the morbidity and mortality in patients with PAD
Pneumococcal Immunization Reduces Neurological and Hepatic Symptoms in a Mouse Model for Niemann-Pick Type C1 Disease
Niemann-Pick type C1 (NPC1) disease is caused by a deleterious mutation in the Npc1 gene, causing lysosomal accumulation of unesterified cholesterol and sphingolipids. Consequently, NPC1 disease patients suffer from severe neurovisceral symptoms which, in the absence of effective treatments, result in premature death. NPC1 disease patients display increased plasma levels of cholesterol oxidation products such as those enriched in oxidized low-density lipoprotein (oxLDL), a pro-inflammatory mediator. While it has been shown that inflammation precedes and exacerbates symptom severity in NPC1 disease, it is unclear whether oxLDL contributes to NPC1 disease progression. In this study, we investigated the effects of increasing anti-oxLDL IgM autoantibodies on systemic and neurological symptoms in an NPC1 disease mouse model. For this purpose, Npc1 nih mice were immunized with heat-inactivated S. pneumoniae, an immunogen which elicits an IgM autoantibody-mediated immune response against oxLDL. Npc1 nih mice injected with heat-inactivated pneumococci displayed an improved hepatic phenotype, including liver lipid accumulation and inflammation. In addition, regression of motor skills was delayed in immunized Npc1 nih . In line with these results, brain analyses showed an improved cerebellar phenotype and neuroinflammation in comparison with control-treated subjects. This study highlights the potential of the pneumococcal immunization as a novel therapeutical approach in NPC1 disease. Future research should investigate whether implementation of this therapy can improve life span and quality of life of NPC1 disease patients
Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells.
Atherosclerosis is initiated and sustained by hypercholesterolemia, which results in the generation of oxidized LDL (OxLDL) and other metabolic byproducts that trigger inflammation. Specific immune responses have been shown to modulate the inflammatory response during atherogenesis. The sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of the functions of several immune cells, including myeloid cells and B-1 cells. Here, we show that deficiency of Siglec-G in atherosclerosis-prone mice inhibits plaque formation and diet-induced hepatic inflammation. We further demonstrate that selective deficiency of Siglec-G in B cells alone is sufficient to mediate these effects. Levels of B-1 cell-derived natural IgM with specificity for OxLDL were significantly increased in the plasma and peritoneal cavity of Siglec-G-deficient mice. Consistent with the neutralizing functions of OxLDL-specific IgM, Siglec-G-deficient mice were protected from OxLDL-induced sterile inflammation. Thus, Siglec-G promotes atherosclerosis and hepatic inflammation by suppressing protective anti-inflammatory effector functions of B cells
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Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.
Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis
Oxidation-Specific Epitopes (OSEs) Dominate the B Cell Response in Murine Polymicrobial Sepsis
In murine abdominal sepsis by colon ascendens stent peritonitis (CASP), a strong increase in serum IgM and IgG antibodies was observed, which reached maximum values 14 days following sepsis induction. The specificity of this antibody response was studied in serum and at the single cell level using a broad panel of bacterial, sepsis-unrelated as well as self-antigens. Whereas an antibacterial IgM/IgG response was rarely observed, studies at the single-cell level revealed that IgM antibodies, in particular, were largely polyreactive. Interestingly, at least 16% of the IgM mAbs and 20% of the IgG mAbs derived from post-septic mice showed specificity for oxidation-specific epitopes (OSEs), which are known targets of the innate/adaptive immune response. This identifies those self-antigens as the main target of B cell responses in sepsis
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