Monocytes from systemic lupus erythematous patients are severely altered in phenotype and lineage flexibility

Steinbach, Falko; Henke, Fabiola; Krause, B.; Thiele, Bernhard; Burmester, Gerd‐Rüdiger; Hiepe, Falk

doi:10.1136/ard.59.4.283

Cited by 86 publications

(64 citation statements)

References 24 publications

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“…Increased monocyte apoptosis has been described and these results may reflect fewer monocyte cells rather than decreased expression of CD14 on an individual monocyte [42]. Interestingly, this same study identified increased spontaneous TNFα production from patients compared to controls [41], which was not seen in the current study. Intracellular flow cytometry may not have been sufficiently sensitive to detect the spontaneous secretion.…”

Section: Discussionsupporting

confidence: 45%

“…Traditional surface marker expression has not been markedly different in patients and controls in some studies, although receptors for immune complexes are down-regulated, perhaps due to internalization [39;40;41]. One study using single color flow cytometry, found decreased CD14 expression and decreased DR expression [41]. Increased monocyte apoptosis has been described and these results may reflect fewer monocyte cells rather than decreased expression of CD14 on an individual monocyte [42].…”

Section: Discussionmentioning

confidence: 99%

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The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

Sullivan

Suriano

Dietzmann

et al. 2007

Clinical Immunology

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In systemic lupus erythematosus, TNFα is elevated in the serum and correlates with disease activity and triglyceride levels. The stimuli that drive TNFα in this setting are incompletely understood. This study was designed to evaluate monocyte chromatin at the TNFα locus to identify semi-permanent changes that might play a role in altered expression of TNFα. SLE patients with relatively quiescent disease (mean Physician Global Assessment=0.6) and healthy controls were recruited for this study. TNFα expression was measured by intracellular cytokine staining of different monocyte subsets in patients (n=24) and controls (n=12). Histone acetylation at the TNFα locus was measured by chromatin immunoprecipitation using a normalized quantitative PCR in patients (n=46) and controls (n=24). There were no differences in the overall fractions of cells expressing CD14 in SLE patients compared to controls, however, the fraction of DR+/CD16+ cells expressing CD14 was slightly higher as was true in the monocyte subset defined by DR+/CD11b+. Within the monocyte population defined by physical characteristics and DR+/CD14+, TNFα expressing cells were more frequent in SLE patients compared to controls. Both the fraction of positive cells and the mean fluorescence intensity were higher in patients than controls. Consistent with this was the finding that monocytes from patients had increased TNFα transcripts and more highly acetylated histones at the TNFα locus compared to controls. Furthermore, patients with the highest levels of TNFα histone acetylation were more likely to have had consistently elevated erythrocyte sedimentation rates, and to have required cytotoxic use. Histone acetylation, associated with increased transcriptional competence of TNFα, may play a role in certain inflammatory aspects of the disease.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 99%

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

Sullivan

Suriano

Dietzmann

et al. 2007

Clinical Immunology

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“…Based on the present findings, it becomes important to evaluate the extent to which more exuberant APC function may also underlie the T cell hyperactivity noted in other lupus models. Finally, T cell hyperactivity, including several biochemical abnormalities that correlate with T cell hyperresponsiveness, and aberrant DC function have also been documented in human lupus (1,(60)(61)(62)(63)(64)(65)(66)(67). The current findings raise the possibility that the T cell phenotypes noted in human SLE may also be influenced by intrinsic differences in DC/myeloid cell function, in addition to possible T cell-intrinsic anomalies (65)(66)(67).…”

Section: Discussionmentioning

confidence: 73%

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

et al. 2005

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Sle3 is an NZM2410-derived lupus susceptibility locus on murine chromosome 7. Congenic recombination has resulted in a novel mouse strain, B6.Sle3, associated with serum antinuclear autoantibodies (ANAs), T cell hyperactivity, and elevated CD4/CD8 ratios. An OVA-specific TCR transgene was used as a tool to demonstrate that Sle3 facilitated heightened T cell expansion in vitro, and in vivo, following antigen challenge. Indeed, continued T cell expansion was noted even in response to a tolerogenic signal. However, these phenotypes did not appear to be T cell intrinsic but were dictated by hyperstimulatory B6.Sle3 APCs. Importantly, B6.Sle3-derived DCs and macrophages appeared to be significantly more mature/activated, less apoptotic, and more proinflammatory and were better at costimulating T cells in vitro, compared with the B6 counterparts. Finally, the adoptive transfer of B6.Sle3-derived DCs into healthy B6 recipients elicited increased CD4/CD8 ratios and serum ANAs, 2 cardinal Sle3-associated phenotypes. We posit that their heightened expression of various costimulatory molecules, including CD80, CD106, I-A b , and CD40, and their elevated production of various cytokines, including IL-12 and IL-1β, may explain why Sle3-bearing DCs may be superior at breaching self tolerance. These studies provide mechanistic evidence indicating that intrinsic abnormalities in DCs and possibly other myeloid cells may dictate several of the phenotypes associated with systemic lupus, including ANA formation and T cell hyperactivity.

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“…Beside the appearance and high level of various pathologic autoantibodies (e.g. anti-ds-DNA which correlates to the disease activity) and immunocomplexes, the abnormal antigen-receptor signalling events in lupus T and B lymphocytes and monocytes are manifested at the level of signal transduction [2][3][4][5][6][7]. Recently, a decrease was observed in the peripheral ratio (percent) of CD4 þ CD25 þ regulatory T cells in patients with clinically active SLE [8,9].…”

Section: Introductionmentioning

confidence: 99%

The severity of systemic lupus erythematosus negatively correlates with the increasing number of CD4⁺CD25^highFoxP3⁺regulatory T cells during repeated plasmapheresis treatments of patients

et al. 2007

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased pathologic autoantibody production. A decrease in the number of CD4+CD25(high)FoxP3+ regulatory T cells can play a key role in the loss of tolerance to self antigens. Our aim was to determine the absolute number of peripheral CD4+CD25(high)FoxP3+ T cells in 44 patients with SLE, furthermore, to measure the changes in the number of CD+CD25(high)FoxP3+ T cells in 5 patients with severe SLE treated with repeated plasmapheresis for 4-6 days in comparison to the changes in the activity of disease (SLEDAI). Percent of CD4+CD25(high)FoxP3+ T cells were measured by flow cytometry. The absolute number of peripheral CD4+CD25(high)FoxP3+ T cells was significantly decreased in the 44 patients with SLE compared to the healthy controls n = 32 (0.012 +/- 0.006 vs. 0.038 +/- 0.017 G/L, p < 0.05). In the 5 patients with severe SLE the repeated plasmapheresis treatments increased the peripheral number of CD4+CD25(high)FoxP3+ T cells. As the number of CD4+CD25(high)FoxP3+ T cells increased during the treatment, the activity of disease (the value of SLE activity index) decreased. In the peripheral blood of SLE patients not only the ratio was decreased (as it was published earlier) but also the absolute number of these regulatory T cells. The repeated plasmapheresis treatments of SLE patients induced a significant increase in the number of peripheral CD4+CD25(high)FoxP3+ T cells in parallel to the decrease in the values of SLEDAI (the activity of disease). This phenomenon is, among others, possibly due to the elimination of interpheron-alpha and lymphocytotoxic antibodies during plasmapheresis.

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Monocytes from systemic lupus erythematous patients are severely altered in phenotype and lineage flexibility

Cited by 86 publications

References 24 publications

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

The severity of systemic lupus erythematosus negatively correlates with the increasing number of CD4⁺CD25^highFoxP3⁺regulatory T cells during repeated plasmapheresis treatments of patients

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Monocytes from systemic lupus erythematous patients are severely altered in phenotype and lineage flexibility

Cited by 86 publications

References 24 publications

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

The severity of systemic lupus erythematosus negatively correlates with the increasing number of CD4+CD25highFoxP3+regulatory T cells during repeated plasmapheresis treatments of patients

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The severity of systemic lupus erythematosus negatively correlates with the increasing number of CD4⁺CD25^highFoxP3⁺regulatory T cells during repeated plasmapheresis treatments of patients