Lymphopenia In Systemic Lupus Erythematosus

Rivero, S; Díaz-Jouanen, E; Alarcón‐Segovia, Donato

doi:10.1002/art.1780210302

Cited by 136 publications

(32 citation statements)

References 14 publications

(3 reference statements)

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“…This granulocyte signature was present in about 50% of the SLE patients profiled and included but was not limited to the following genes: AZU, DEFA1, DEFA4, ELA2, MMP8, MMP9, RNAS2, MPO, CAMP, FCAR, and CYBB (Figure 1). The downregulation of T and B cell gene signatures was also observed in WB of SLE patients (Figure 1), and is consistent with the observation of lymphopenia in the peripheral blood of SLE patients that has been previously reported in the literature [13, 20]. Table 3 lists the 50 most downregulated transcripts observed in WB of SLE patients.…”

Section: Resultssupporting

confidence: 89%

Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus

Yao¹,

Higgs²,

Morehouse³

et al. 2009

Human Genomics and Proteomics

116

158

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To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-α) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-α/β-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-α/β-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-α mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-α mAb or anti-IFN-α receptor mAb showed that anti-IFN-α mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-α, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-α as a therapeutic target for SLE.

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Section: Resultssupporting

confidence: 89%

Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus

Yao¹,

Higgs²,

Morehouse³

et al. 2009

Human Genomics and Proteomics

116

158

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“…Finally, patients with inactive disease had a significantly lower percentage of CD4 + T cells than in HCs (11.79 ± 0.80%, N = 52 vs. 17.12 ± 0.71%, N = 83, respectively, P < 0.0001). These results confirm earlier reports [3-5] that SLE patients present with CD4 + T cell leucopenia correlated with disease activity and showed that it is accentuated by steroid and immunosuppressive treatment, which is by itself associated with disease activity.…”

Section: Resultssupporting

confidence: 92%

“…Multiple studies have shown that these autoantibodies are T cell-dependent with autoreactive CD4 + T cells providing co-stimulatory signals and cytokines such as IL-4 and IL-21 to the autoreactive B cells [1,2]. The CD4 + T cells of SLE patients present many functional defects, which include a reduced number of circulating cells that is associated with disease activity [3-5], impaired signaling [6] and increased spontaneous activation coupled with a hypo-responsiveness upon reactivation [7,8]. …”

Section: Introductionmentioning

confidence: 99%

Defective response of CD4+ T cells to retinoic acid and TGFβ in systemic lupus erythematosus

et al. 2011

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IntroductionCD25+ FOXP3+ CD4+ regulatory T cells (Tregs) are induced by transforming growth factor β (TGFβ) and further expanded by retinoic acid (RA). We have previously shown that this process was defective in T cells from lupus-prone mice expressing the novel isoform of the Pbx1 gene, Pbx1-d. This study tested the hypothesis that CD4+ T cells from systemic lupus erythematosus (SLE) patients exhibited similar defects in Treg induction in response to TGFβ and RA, and that PBX1-d expression is associated with this defect.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from 142 SLE patients and 83 healthy controls (HCs). The frequency of total, memory and naïve CD4+ T cells was measured by flow cytometry on fresh cells. PBX1 isoform expression in purified CD4+ T cells was determined by reverse transcription polymerase chain reaction (RT-PCR). PBMCs were stimulated for three days with anti-CD3 and anti-CD28 in the presence or absence of TGFβ and RA. The expression of CD25 and FOXP3 on CD4+ T cells was then determined by flow cytometry. In vitro suppression assays were performed with sorted CD25+ and CD25- FOXP3+ T cells. CD4+ T cell subsets or their expansion were compared between patients and HCs with two-tailed Mann-Whitney tests and correlations between the frequencies of two subsets were tested with Spearman tests.ResultsThe percentage of CD25- FOXP3+ CD4+ (CD25- Tregs) T cells was greater in SLE patients than in HCs, but these cells, contrary to their matched CD25+ counterparts, did not show a suppressive activity. RA-expansion of TGFβ-induced CD25+ Tregs was significantly lower in SLE patients than in HCs, although SLE Tregs expanded significantly more than HCs in response to either RA or TGFβ alone. Defective responses were also observed for the SLE CD25- Tregs and CD25+ FOXP3- activated CD4+ T cells as compared to controls. PBX1-d expression did not affect Treg induction, but it significantly reduced the expansion of CD25- Tregs and prevented the reduction of the activated CD25+ FOXP3- CD4+ T cell subset by the combination of TGFβ and RA.ConclusionsWe demonstrated that the induction of Tregs by TGFβ and RA was defective in SLE patients and that PBX1-d expression in CD4+ T cells is associated with an impaired regulation of FOXP3 and CD25 by TGFβ and RA on these cells. These results suggest an impaired integration of the TGFβ and RA signals in SLE T cells and implicate the PBX1 gene in this process.

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“…The increased frequency of CD8 + T cells specific for lytic EBV antigens is most likely due to recurrent EBV replication. However, the elevated frequency is counterbalanced by a global T cell lymphopenia, which is a common clinical feature of SLE [25]. Furthermore, functional impairment at the single-cell level coincides with a diminished absolute number of functional EBV-specific CD8 + T cells in SLE patients.…”

Section: Discussionmentioning

confidence: 99%

Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

et al. 2011

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Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.

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Lymphopenia In Systemic Lupus Erythematosus

Cited by 136 publications

References 14 publications

Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus

Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus

Defective response of CD4+ T cells to retinoic acid and TGFβ in systemic lupus erythematosus

Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

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