Neutrophil Extracellular Traps That Are Not Degraded in Systemic Lupus Erythematosus Activate Complement Exacerbating the Disease (original) (raw)
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Frontiers in Immunology, 2012
Neutrophils are the most abundant leukocytes in circulation and represent one of the first lines of defense against invading pathogens. Neutrophils possess a vast arsenal of antimicrobial proteins, which can be released from the cell by a death program termed NETosis. Neutrophil extracellular traps (NETs) are web-like structures consisting of decondensed chromatin decorated with granular and cytosolic proteins. Both exuberant NETosis and impaired clearance of NETs have been implicated in the organ damage of autoimmune diseases, such as systemic lupus erythematosus (SLE), small vessel vasculitis (SVV), and psoriasis. NETs may also represent an important source of modified autoantigens in SLE and SVV. Here, we review the autoimmune diseases linked to NETosis, with a focus on how modified proteins externalized on NETs may trigger loss of immune tolerance and promote organ damage.
Neutrophil Extracellular Traps-DNase Balance and Autoimmunity
Cells
Neutrophil extracellular traps (NETs) are macromolecular structures programmed to trap circulating bacteria and viruses. The accumulation of NETs in the circulation correlates with the formation of anti-double-stranded (ds) DNA antibodies and is considered a causative factor for systemic lupus erythematosus (SLE). The digestion of DNA by DNase1 and DNases1L3 is the rate- limiting factor for NET accumulation. Mutations occurring in one of these two DNASE genes determine anti-DNA formation and are associated with severe Lupus-like syndromes and lupus nephritis (LN). A second mechanism that may lead to DNase functional impairment is the presence of circulating DNase inhibitors in patients with low DNase activity, or the generation of anti-DNase antibodies. This phenomenon has been described in a relevant number of patients with SLE and may represent an important mechanism determining autoimmunity flares. On the basis of the reviewed studies, it is tempting to suppose that the blockade ...
Lupus science & medicine, 2014
To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE). The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (...
Experimental Dermatology, 2019
Neutrophils are major players at sites of tissue inflammation and use different mechanisms to fight against bacterial infections and/ or alter the inflammatory milieu. In 2004, Brinkmann et al discovered a new mechanism of action whereby activated neutrophils release their contents in a web-like structure forming traps that bind and kill bacteria extracellularly. [1] These neutrophil extracellular traps or NETs contain DNA, histones and neutrophil proteins such as myeloperoxidase and neutrophil elastase. They can also be a major source of self-molecules implicated in autoimmunity and autoinflammation. [2] This relationship between NETosis and autoimmunity has been demonstrated in a number rheumatic diseases such as small vessel vasculitis, rheumatoid arthritis, Behçet's disease, gout and systemic lupus erythematosus. [3] Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the presence of antinuclear and anti-double-stranded DNA autoantibodies. In addition, autoantibodies against histones are found in drug-induced lupus erythematosus. [4] Interestingly, those nuclear self-antigens are components of NETs. Numerous studies on human samples and murine models have shown that NETs contribute to the pathogenesis of systemic lupus. [5] In SLE patients, circulating neutrophils have increased ability to release NETs, and those NETs contain DNA-antimicrobial peptide (like
PloS one, 2016
Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to con...
Clinical and Developmental Immunology, 2012
CD55, CD59, CD46, and CD35 are proteins with complement regulatory (Creg) properties that ensure cell and tissue integrity when this system is activated. The aim of this study was to evaluate the Creg expression on peripheral blood cells from SLE patients and its association with cytopenia and disease activity. Flow cytometric analyses were performed on blood cells from 100 SLE patients and 61 healthy controls. Compared with healthy controls, we observed in SLE patients with lymphopenia and neutropenia decreased expression of CD55, CD59, and CD46 (P<0.05). In SLE patients with anemia, CD59 and CD35 were decreased on red blood cells. Furthermore, there was a negative correlation between CD55 and CD59 on neutrophils and the disease activity. The results suggest there is an altered pattern of Creg expression on the peripheral blood cells of SLE patients, and the expression is correlated with disease activity and/or with activation of the complement system.
Cell-Bound Complement Biomarkers for Systemic Lupus Erythematosus: From Benchtop to Bedside
Rheumatic Disease Clinics of North America, 2010
Systemic lupus erythematosus (SLE) is arguably the most clinically and serologically diverse autoimmune disease (1,2). Currently available information suggests that intricate interactions between environmental factors, hormonal factors, and disease susceptibility genes may predispose an individual to develop aberrant immune responses leading to SLE. Such aberrant responses, characterized by polyclonal activation of autoreactive lymphocytes, autoantibody production, immune complex formation, and complement activation, lead to acute and chronic inflammation in various tissue and organ systems. Owing to its complex etiopathogenesis, heterogeneous presentation, and unpredictable course, SLE remains one of the greatest challenges to both investigators and physicians. Currently, the diagnosis of SLE is primarily based on the presence or absence of American College of Rheumatology (ACR) criteria (3, 4). Disease activity in SLE patients is often assessed using indices such as the Systemic Lupus disease Activity Index (SLEDAI) (5), the Systemic Lupus Activity Measurement (SLAM) (6,7), and the British Isles Lupus Assessment Group (BILAG) index (8). The lack of easy-tomeasure, reliable and specific biomarkers for SLE not only hampers precise assessment of disease activity and accurate evaluation of response to treatment, but it also impedes the development of novel therapeutics targeting key pathogenic factors. Therefore, there is an urgent need for reliable, specific biomarkers in not only lupus patient care but also in research.