Background— Immunoglobulin M (IgM) natural antibodies bind oxidatively-modified low-density lipoprotein (LDL) and apoptotic cells and have been implicated as being important for protection against atherosclerosis. We have directly investigated the requirement for IgM by studying the effects of IgM deficiency in LDL receptor–deficient ( Ldlr ^−/− ) mice. Methods and Results— Mice deficient in serum IgM (sIgM) or complement C1q were crossed with Ldlr ^−/− mice and studied on both low-fat and high-fat semisynthetic diets. On both diets, en face and aortic root atherosclerotic lesions in sIgM.Ldlr ^−/− mice were substantially larger and more complex, with accelerated cholesterol crystal formation and increased smooth muscle cell content in aortic root lesions. Combined C1q and IgM deficiency had the same effect as IgM deficiency alone. Increased apoptosis was observed in aortic root lesions of both sIgM.Ldlr ^−/− and C1qa.Ldlr ^−/− mice. Because lesions were significantly larger in IgM-deficient mice than in the absence of C1q, IgM protective mechanisms appear to be partially independent of classical pathway activation and apoptotic cell clearance. Levels of IgG antibodies against copper-oxidized LDL were lower in sIgM.Ldlr ^−/− mice fed a high-fat diet, suggesting compensatory consumption of IgG in the absence of IgM. Conclusions— This study provides direct evidence that IgM antibodies play a central role in protection against atherosclerosis. The mechanism appears to be at least partly independent of classical pathway complement activation by C1q.

The clinical manifestations of gout are due to interactions between monosodium urate (MSU) crystals and local tissues. This review article outlines recent advances in the understanding of the mechanisms of inflammation in gout. We focus on the cellular response to MSU crystals during acute arthritis, termination of the acute attack and maintenance of asymptomatic hyperuricaemia, and chronic tophaceous disease. We then propose a unifying model of gout involving the differential role of mononuclear phagocytes in the regulation of the inflammatory response to MSU crystals.

Objective: It has previously been shown that as monocytes differentiate into macrophages, they lose the ability to secrete proinflammatory cytokines in response to monosodium urate monohydrate (MSU) crystals. The purpose of this study was to investigate whether MSU crystals induce macrophages to secrete antiinflammatory factor instead.Methods: Human monocyte or macrophage isolates were prepared from samples obtained from healthy volunteer donors either by differentiation of blood monocytes in vitro or by collecting cells from skin blisters during the early or late phase of the dermal inflammatory response to cantharidin. Monocyte or macrophage isolates were then incubated with MSU crystals for 24 hours, and culture supernatants were assayed for candidate antiinflammatory mediators (by enzyme‐linked immunosorbent assay) and for the capacity to activate or suppress endothelial cell E‐selectin expression and secondary neutrophil recruitment under shear flow.Results: Analysis of supernatants from in vitro–differentiated macrophages revealed that transforming growth factor β1 (TGFβ1) was induced following MSU crystal stimulation (mean ± SEM 1.50 ± 0.24 ng/ml/10⁶ cells), but there was no evidence of interleukin‐10 (IL‐10), IL‐1 receptor antagonist, or tumor necrosis factor (TNF) receptor p55 release. Macrophage TGFβ1 significantly suppressed endothelial cell E‐selectin expression and secondary neutrophil capture on endothelial monolayers stimulated with supernatants from MSU‐treated monocytes. Leukocytes isolated from resolving (40‐hour) skin blisters similarly elaborated TGFβ1 when challenged with MSU crystals (0.66 ± 1.3 ng/ml/10⁵ CD14+ cells). In contrast, cells isolated from acute (16‐hour) skin blisters secreted TNFα (0.49 ± 0.08 ng/ml/10⁵ CD14+ cells) but no detectable TGFβ1.Conclusion: These data provide further support for the concept that differentiated macrophages play a protective role in the pathophysiology of gout, and they identify macrophage TGFβ1 as a mediator of paracrine suppression during the resolution phase of inflammation.

Although it has long been recognized that atherosclerotic lesions show evidence of complement activation, the functional roles of the complement system in atherogenesis are not yet fully resolved. This article highlights recent publications on the complement system in the atherosclerosis field. There have been a number of recent papers reporting on the association of complement proteins and complement regulators with high density lipoproteins, complement activation by enzymatically-modified LDL, signalling pathways downstream of C3a and C5a receptors and membrane C5b-9 assembly, and the prevention of C5b-9 assembly on endothelial cells via upregulation of CD59 expression in response to arterial laminar flow. C1q has been found to play a protective role in early lesion formation in LDL receptor deficient mice, and Crry-Ig and soluble C1 inhibitor have both been shown to have therapeutic effects in models of vascular injury in ApoE deficient mice. The possibility that the Y402H Factor H polymorphism influences atherosclerosis has been supported in a recent paper showing increased risk in white hypertensive individuals. The articles that have emerged over the last year highlight the relevance of the complement system to the atherosclerosis field.

Antibodies to oxidized LDL (oxLDL) may be associated with improved outcomes in cardiovascular disease. However, analysis is restricted by heterogenous study design and endpoints. Our objective was to conduct a comprehensive systematic review assessing anti-oxLDL antibodies in relation to coronary artery disease (CAD). Through a systematic literature search, we identified all studies assessing the relationship of either, IgG or IgM ox-LDL/ copper-oxLDL/ malondialdehyde-LDL, with coronary atherosclerosis or cardiovascular events in populations with, and without, established CAD. Systematic review best practices were adhered to and study quality was assessed. An initial electronic database search identified 2059 records, which was subsequently followed by abstract and full-text review. Finally, we included 18 studies with over 1811 patients with CAD. The studies varied according to populations studied, conventional cardiovascular risk factors and interventional modalities used to assess CAD. IgM anti-oxLDL antibodies were found to indicate protection from more severe CAD and possibly cardiovascular events, whilst the relationship with IgG is more complex and difficult to elucidate, with studies reporting divergent results. In this systematic review, there is evidence that suggests a relationship between anti-oxLDL antibodies and CAD, especially for the IgM subclass. However, further studies, with well-characterized prospective cohorts, will be important to clarify these associations.

We aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies against malondialdehyde-conjugated low-density lipoprotein (MDA-LDL), can improve cardiovascular risk discrimination. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized 9098 patients in the UK and Ireland into the Blood Pressure-Lowering Arm. 485 patients that had cardiovascular (CV) events over 5.5years were age and sex matched with 1367 controls. Higher baseline total serum IgG, and to a lesser extent IgM, were associated with decreased risk of CV events (IgG odds ratio (OR) per one standard deviation (SD) 0.80 [95% confidence interval, CI 0.72,0.89], p<0.0001; IgM 0.83[0.75,0.93], p=0.001), and particularly events due to coronary heart disease (CHD) (IgG OR 0.66 (0.57,0.76); p<0.0001, IgM OR 0.81 (0.71,0.93); p=0.002). The association persisted after adjustment for a basic model with variables in the Framingham Risk Score (FRS) as well as following inclusion of C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NtProBNP). IgG and IgM antibodies against MDA-LDL were also associated with CV events but their significance was lost following adjustment for total serum IgG and IgM respectively. The area under the receiver operator curve for CV events was improved from the basic risk model when adding in total serum IgG, and there was improvement in continuous and categorical net reclassification (17.6% and 7.5% respectively) as well as in the integrated discrimination index. High total serum IgG levels are an independent predictor of freedom from adverse cardiovascular events, particularly those attributed to CHD, in patients with hypertension.