Monocyte apoptosis in patients with active lupus

Richardson, Bruce C.; Yung, Raymond; Johnson, Kent J.; Rowse, Paul E.; Lalwani, Narendra D.

doi:10.1002/art.1780390827

Cited by 51 publications

(28 citation statements)

References 12 publications

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“…However, it is also of note that, as in previous studies, we have used young (8-to 10-wk-old), prediseased mice. In addition, previous studies have detected higher levels of apoptosis in monocytes and macrophages from SLE patients, which would be consistent with the reduced uptake of apoptotic cells (45,54) observed in our assays. However, in the present study there was no detectable difference in annexin V binding to resident macrophages from MRL/Mp mice and the control strains either ex vivo or in vitro (data not shown).…”

Section: Discussionsupporting

confidence: 92%

Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells

Potter

Cortés-Hernández

Quartier

et al. 2003

The Journal of Immunology

159

115

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Deficiency of complement in humans and mice is associated with the development of lupus and with abnormal repair of inflammatory and immune complex-mediated tissue injury. Here we ask whether similar defects in the resolution of inflammation are found in mice prone to spontaneous lupus. We compared the response to an i.p. injection of thioglycolate between two lupus-prone strains (MRL/Mp and NZB/W) and two non lupus-prone strains of mice (C57BL/6 and BALB/c). In all four strains the influx of polymorphonuclear neutrophils (PMN) was similar. However, by 96 h clearance of PMN in the control strains was complete, whereas in the autoimmune-prone strains PMN were still detectable. The number of mononuclear cells recruited was markedly reduced in the lupus-prone strains compared with the controls, and their phenotype was different. The lupus-prone strains had significantly fewer elicited macrophages that were CD11b-high and Ly6C-negative. In lupus-prone mice at 24 h there was a significantly increased number of apoptotic PMN free in the peritoneum, accompanied by a reduced percentage of macrophages containing apoptotic bodies, suggesting a defect in their uptake. An impaired ability of resident peritoneal macrophages from lupus-prone mice to engulf apoptotic cells was demonstrated by in vivo and in vitro cell clearance assays. These observations indicate that lupus-prone strains have an abnormal inflammatory response to thioglycolate and an intrinsic impairment in apoptotic cell uptake. These findings have implications for the initiation of autoimmunity, as lupus autoantigens are expressed on dying cells, and impaired disposal of these could enhance the development of autoimmunity.

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Section: Discussionsupporting

confidence: 92%

Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells

Potter

Cortés-Hernández

Quartier

et al. 2003

The Journal of Immunology

159

115

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“…The same cells induce anti-DNA Abs in vivo (17), suggesting that this killing might contribute to the autoantibody response by providing a source of antigenic DNA. In support of this, patients with idiopathic systemic lupus erythematosus have increased numbers of circulating apoptotic monocytes (11), which may serve a similar function. Now that candidates for the responsible molecules have been identified, it is possible to test whether inhibiting D10-mediated M killing in vivo prevents the development of autoantibodies.…”

Section: Discussionmentioning

confidence: 80%

“…We reported that the process of CD4 ϩ T cell activation can result in apoptosis of the stimulating M, and proposed that this mechanism could be important in M homeostasis as well as serving to down-regulate immune responses and eliminate M infected with intracellular organisms (8). We also reported that a more promiscuous M killing by autoreactive CD4 ϩ T cells may provide a source of antigenic nucleic acids in a lupus model (9,10) and in patients with active lupus (11,12), further emphasizing the importance of this phenomenon. The mechanisms involved in this response are incompletely defined.…”

mentioning

confidence: 98%

TRAIL (Apo2 Ligand) and TWEAK (Apo3 Ligand) Mediate CD4+ T Cell Killing of Antigen-Presenting Macrophages

Kaplan

Ray

et al. 2000

The Journal of Immunology

Self Cite

122

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The human marrow produces ∼1010 monocytes daily, and this production must be balanced by a similar rate of destruction. Monocytes/macrophages can undergo apoptosis after activating CD4+ T cells, suggesting one mechanism that may contribute to macrophage homeostasis. Previous reports indicate that Fas-Fas ligand interactions are the principle molecules mediating this response. However, D10, an Iak-restricted cloned Th2 line, will similarly induce apoptosis in Ag-presenting macrophages, and D10 cells lack Fas ligand. To confirm that D10 cells kill macrophages through Fas-independent pathways, D10 cells were shown to kill MRL lpr/lpr (Iak) macrophages in an Ag-dependent fashion, indicating additional mechanisms. Recent reports demonstrate that TNF-related apoptosis-inducing ligand (TRAIL), interacting with Apo2, and TNF-like weak inducer of apoptosis (TWEAK), interacting with Apo3, will induce apoptosis in some cells. Using Abs to TRAIL and an Apo3-IgG Fc fusion protein, we demonstrated that D10 cells express both TRAIL and TWEAK. The Apo3 fusion protein, but not human IgG, inhibited D10-induced macrophage apoptosis, as did anti-TRAIL. Further studies demonstrated that AE7, a cloned Th1 line, and splenic T cells express TWEAK, TRAIL, and Fas ligand, and inhibiting these molecules also inhibited macrophage killing. These results indicate that D10 cells induce macrophage apoptosis through TRAIL- and TWEAK-dependent pathways. Because normal T cells also express these molecules, these results support the concept that T cells have multiple pathways by which to induce macrophage apoptosis. These pathways may be important in immune processes such as macrophage homeostasis as well as in down-regulation of immune responses and elimination of macrophages infected with intracellular organisms.

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“…We believe there is a separate subpopulation of splenocytes, apart from autoreactive T cells, which undergoes spontaneous death when cultured. Several studies of peripheral blood in lupus or systemic sclerosis patients also uncovered apoptotic lymphocytes or monocytes upon placement in culture [92][93][94][95][96][97][98]. The findings suggest that other immune cell populations besides autoreactive T cells are altered in autoimmunity and, consequently, that other strategies may been neededabove and beyond TNF-a therapy.…”

mentioning

confidence: 94%

The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis

Kodama

Davis

Faustman

2005

CMLS, Cell. Mol. Life Sci.

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Excess levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-alpha levels are deleterious, several anti-TNF-alpha therapies are now available to block the action of TNF-alpha in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-alpha antagonists have provided clinical benefit to many patients, but their use also is accompanied by new or aggravated forms of autoimmunity. Here we propose a mechanistically based hypothesis for the adverse events observed with TNF-alpha antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-alpha activity as a treatment for some forms of autoimmunity. Activation defects in the transcription factor nuclear factor kappaB leave autoreactive T cells sensitive to TNF-alpha-induced apoptosis. Treatment with TNF-alpha, by destroying autoreactive T cells, appears to be a highly targeted strategy to interrupt the pathogenesis of type 1 diabetes, lupus and certain forms of autoimmunity.

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Monocyte apoptosis in patients with active lupus

Cited by 51 publications

References 12 publications

Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells

Lupus-Prone Mice Have an Abnormal Response to Thioglycolate and an Impaired Clearance of Apoptotic Cells

TRAIL (Apo2 Ligand) and TWEAK (Apo3 Ligand) Mediate CD4+ T Cell Killing of Antigen-Presenting Macrophages

The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis

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