Apoptosis, subcellular particles, and autoimmunity

Cline, Amy M.; Radic, Marko

doi:10.1016/j.clim.2004.02.017

Cited by 84 publications

(60 citation statements)

References 79 publications

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“…Consequently, the proportion of circulating cell-derived MPs with surface-bound IgG was significantly increased in the SLE group (median [5th-95th percentile] 3.5% [0. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].3%] in the SLE patient group versus 0.4% [0.02-4.3%] in the healthy control group; P Ͻ 0.0001).…”

Section: Resultsmentioning

confidence: 99%

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

Nielsen

Østergaard

Stener

et al. 2012

Arthritis & Rheumatism

154

146

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Objective. To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in patients with systemic lupus erythematosus (SLE) and to determine whether immunoglobulin and C1q levels are correlated with clinical and serologic parameters.Methods. Sixty-eight clinically well-characterized SLE patients, 38 healthy controls, 6 patients with systemic sclerosis (SSc), and 6 patients with rheumatoid arthritis (RA) were included. The numbers of annexin V-binding MPs displaying IgG, IgM, or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP IgG load was determined by flow cytometric analysis of all samples from SLE patients and healthy controls.Results. SLE patients had significantly increased total and relative numbers of IgG-positive MPs (P ‫؍‬ 0.0004), with a much higher average IgG load per MP (P < 0.0001) than healthy controls. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q levels in SLE patients. In RA and SSc patients, the average IgG load per MP was significantly lower than in SLE patients (P ‫؍‬ 0.006 and P ‫؍‬ 0.05, respectively). Also, the IgM load and C1q load per MP were significantly higher in SLE patients than in the control groups (P < 0.05), except for IgM in the RA group. IgG-positive MPs were significantly associated with the presence of anti-double-stranded DNA, anti-extractable nuclear antigen, and antihistone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG load per MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and complement consumption. Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide range of clinical manifestations (1). One of the serologic hallmarks of SLE is the presence of circulating, high-affinity autoantibodies against nuclear constituents (2). These autoantibodies may form circulating proinflammatory immune complexes (ICs) that directly trigger plasmacytoid dendritic cells (PDCs) and the complement system, e.g., in the kidneys (3). Also, IC and autoantibody activation of SLE neutrophils prone to NETosis, i.e., specialized neutrophil cell death, contributes to the sustained PDC activation that is typical of SLE (4,5). The etiology of antinuclear autoimmunity in SLE remains unclear, but persistent, poorly cleared circulating cellular remnants, including microparticles (MPs) and neutrophil extracellular traps, are likely sources of immunogenic autoantigens (6-9). Conclusion. Our findings indicate that circulating cell-derived MPs in SLE patients

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Section: Resultsmentioning

confidence: 99%

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

Nielsen

Østergaard

Stener

et al. 2012

Arthritis & Rheumatism

154

146

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“…We used inhibitors of rho-kinase (Y-27632), myosin light chain kinase (ML-9) or the pan-caspase inhibitor (zVAD-FMK). [18][19][20][21] The use of these inhibitors revealed that formation of ABs depends on the activation of the apoptotic signaling cascade (caspase activation) and the consecutive cytoskeletal activation. Formation of ABs was significantly inhibited by Y-27632 (27.771.8%), ML-9 (59.0710.1%) and most efficiently by zVAD-FMK (99.076.7%) (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

“…17 The process of AB formation has been investigated by several groups during the previous years and surface blebs of various size and content have been described. [18][19][20][21] Surface blebs separate from the cellular remnant and convert into smaller ABs. Throughout this paper, subcellular particles that have separated from apoptozing cells are referred to as ABs.…”

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confidence: 99%

Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis

et al. 2007

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A dysregulation of apoptosis or an ineffective clearance of apoptotic material is suspected to be involved in the pathogenesis of systemic lupus erythematodes. Subcellular fragments such as apoptotic bodies (ABs) have been recognized as modulators of intercellular communication and immune function. In this context, we have been interested whether nuclear and cytoplasmic antigens are relocated into ABs. In the present study, we characterized ABs isolated from apoptozing lymphoblasts. We found an accumulation of the linker-histone (histone 1) as well as the core-histones (histone 2A, histone 2B, histone 3, histone 4) in ABs. Further, they contained DNA, RNA and the ribonuclear protein La/SSB. Proteins such as cytochrome c, HSP 70, prohibitin, p53, nuclear matrix antigen or lamin B were excluded from ABs. The content of ABs differed from that observed in membrane microparticles isolated from viable cells. Formation of ABs occurred early during apoptosis. It was observed before DNAdegradation or phosphatidylserine exposure was detected. ABs were engulfed by monocyte-derived phagocytes. These findings suggest that immunogenic molecules are actively translocated into ABs followed by a rapid engulfment of the latter by environmental phagocytes. In autoimmune diseases, a defect in the clearance of ABs or AB formation may contribute to the development of autoimmunity.

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“…Abnormal or ineffective clearance of apoptotic cells and cellular debris (ie, "efferocytosis") (Vandivier et al 2006), resulting in defective phagocytosis of apoptotic bodies and/or other particulates, have been linked to the development of autoimmunity (Cline and Radic 2004). Hodge et al have shown that alveolar macrophages harvested from the BAL fl uid of patients with COPD had an impaired ability to phagocytose apoptotic epithelial cells in vitro (Hodge et al 2003).…”

Section: Other Autoantigensmentioning

confidence: 99%

Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease

Gadgil

Duncan

2008

COPD

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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US and a major worldwide healthcare problem. The pathophysiologic mechanisms that drive development and progression of this disease are complex and only poorly understood. While tobacco smoking is the primary risk factor, other disease processes also appear to play a role. Components of the innate immune system (eg, macrophages and neutrophils) have long been believed to be important in the development of COPD. More recent evidence also suggests involvement of the adaptive immune system in pathogenesis of this disease. Here we will review the literature supporting the participation of T-cells in the development of COPD, and comment on the potential antigenic stimuli that may account for these responses. We will further explore the prospective contributions of T-cell derived mediators that could contribute to the infl ammation, alveolar wall destruction, and small airway fi brosis of advanced COPD. A better understanding of these complex immune processes will lead to new insights that could result in improved preventative and/or treatment strategies.

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Apoptosis, subcellular particles, and autoimmunity

Cited by 84 publications

References 79 publications

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis

Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease

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