The clinical significance of decreased T cell interleukin‐2 production in systemic lupus erythematosus: Connecting historical dots

Horwitz, David A.

doi:10.1002/art.27538

Cited by 10 publications

(10 citation statements)

References 18 publications

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“…Similarly, impaired cellular immunity in human SLE has also been noted as these lymphocytes can be non-responsive to mitogenic or antigenic stimuli in vitro compared to HCs (13). This defective cellular function is attributed to disease severity/duration, intrinsic T-cell defects, and exhaustion of previously activated cells (13).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, Tregs have also been shown to be significantly expanded in patients with active SLE compared to those with inactive disease and HCs (10–13). Some studies suggest that the defects of Tregs are secondary to the imbalance between auto-aggressive T-cells and Tregs in lupus patients, tipping the balance toward Teffector (Teff) activation, clonal expansion, cell survival, cytokine production, and ultimately, autoimmunity (8, 11, 12).…”

Section: Introductionmentioning

confidence: 99%

“…This defective cellular function is attributed to disease severity/duration, intrinsic T-cell defects, and exhaustion of previously activated cells (13). Interestingly, this expected exhaustion status becomes evident as these cells have reduced proliferation responses to TCR V β-specific super-antigen staphylococcal enterotoxin B (SEB) in chronic autoimmunity or infections (14).…”

Section: Introductionmentioning

confidence: 99%

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Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood-Onset Systemic Lupus Erythematosus

et al. 2017

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BackgroundSeveral studies suggest that defects of regulatory T-cells (Tregs) and impaired cellular immunity are secondary to an imbalance between auto-aggressive T-cells and Tregs in lupus patients. Discrepancies in Tregs and effector T-cells (Teff) in active lupus patients are shown to be restored in patients upon receiving immunosuppressive therapy. Therefore, our main aim was to observe frequencies of these CD4+ T-cell subsets and Tregs/Teff ratio in a new diagnosis of childhood-onset systemic lupus erythematous (cSLE) before and after initiation of therapy. In addition, we monitored T-cell exhaustion status by examining responses to super-antigen staphylococcal enterotoxin B (SEB) and PD-1 expression in this patient.MethodsPhenotyping of CD4+ T-cell subsets was carried out under basal conditions and after SEB stimulation using flow cytometry in one inactive (I-cSLE) and one active cSLE (A-cSLE) patient, as well as a healthy control (HC). The A-cSLE patient was a new diagnosis. Variables were measured at three consecutive time points in the active patient, reflecting various stages of disease activity. Activation status of CD4+ T-cells in the A-cSLE patient was compared to that of the I-cSLE patient and HC. Disease activity was measured by calculating the systemic lupus erythematous disease activity index.ResultsWe found that the A-cSLE patient was not Tregs deficient. The patient had increased frequency of Tregs, and the Tregs/Teff ratio increased when the disease activity became less severe. CD4+ T-cells in the I-cSLE patient and in the A-cSLE patient with milder disease activity had heightened responsiveness to SEB, whereas T-cells were relatively hypo-responsive to SEB in the A-cSLE patient when disease activity was higher. The active patient exhibited higher frequencies of PD-1+ expressing Tregs, Teff, and Tnaïve/mem cells under basal conditions compared to the HC and I-cSLE patient.ConclusionIn the A-cSLE patient, changes in Tregs/Teff ratio correlated better with clinical improvement compared to Tregs frequencies alone and might reflect the restoration of immune homeostasis with therapy. SEB hypo-responsiveness in the A-cSLE patient when disease activity was higher paralleled with findings of greater frequencies of PD-1+ expressing Tregs, Teff, and Tnaïve/mem cells, suggests a possible global exhaustion status of CD4+ T-cells in this patient.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood-Onset Systemic Lupus Erythematosus

et al. 2017

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“…CD8 CTL are absolutely required for control of EBV infection (65) and lupus patients exhibit impaired EBV CD8 CTL responses (66) and higher viral loads (67). As described above, IL-2 is important in CTL maturation and defective IL-2 production is a longstanding and robust finding in both human and murine lupus (46, 68). Although APC defects contribute, lupus T cells exhibit an intrinsic defect in IL-2 production due to an imbalance in the CREM/CREB ratio in the IL-2 promoter region (69).…”

Section: Discussionmentioning

confidence: 94%

“…In human lupus, defective in vitro IL-2 production varies with disease severity (70, 71). In spontaneous lupus mice, defective in vitro IL-2 production increases with age and disease severity (reviewed in (46, 68). In DBA->F1 mice, defective IL-2 production by normal BDF1 host splenocytes is observed as early as two weeks after donor transfer supporting the idea that defective IL-2 production can be induced and is an early marker of lupus activity (32).…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Differences in Donor CD4 T Cell IL-2 Production Influence Severity of Parent-into-F1 Murine Lupus by Skewing the Immune Response Either toward Help for B Cells and a Sustained Autoantibody Response or toward Help for CD8 T Cells and a Downregulatory Th1 Response

Soloviova

Puliaiev

Haas

et al. 2015

The Journal of Immunology

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Using the parent-into-F1 model of induced lupus and (C57Bl/6xDBA2) F1 mice as hosts, we compared the inherent lupus-inducing properties of the two parental strain CD4 T cells. To control for donor CD4 recognition of alloantigen, we used H-2d identical DBA/2 and B10.D2 donor T cells. We demonstrate that these two normal, non-lupus prone parental strains exhibit two different T cell activation pathways in vivo. B10.D2 CD4 T cells induce a strong Th1/CMI pathway characterized by IL-2/IFN-g expression, help for CD8 CTL, skewing of DC subsets towards CD8a DC, coupled with reduced CD4Tfh cells and transient B cell help. By contrast, DBA/2 CD4 T cells exhibit a reciprocal, lupus-inducing pathway characterized by poor IL-2/IFN-g expression, poor help for CD8 CTL, skewing of DC subsets towards pDC coupled with greater CD4 Tfh cells, prolonged B cell activation, autoantibody formation, and lupus-like renal disease. Additionally, two distinct in vivo splenic gene expression signatures were induced. In vitro analysis of TCR signaling revealed defective DBA CD4 T cell induction of NF-κB, reduced degradation of IκBα and increased expression of the NF-κB regulator A20. Thus, attenuated NF-κB signaling may lead to diminished IL-2 production by DBA CD4 T cells. These results indicate that intrinsic differences in donor CD4 IL-2 production and subsequent immune skewing could contribute to lupus susceptibility in humans. Therapeutic efforts to skew immune function away from excessive help for B cells and towards help for CTL may be beneficial.

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The role of microRNA-31 and microRNA-21 as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients

et al. 2016

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by familial aggregation and genetic predisposition. MicroRNAs (MiRNAs) serve as critical biomarkers in lupus patients because of their aberrant expression in different SLE stages. The study aimed to investigate the correlation of miR-31 and miR-21 with IL-2 in SLE patients as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients. Quantitative RT-PCR is carried out to estimate the expressions of miR-31 and miR-21, and IL-2 levels were determined using ELISA in plasma of 40 patients with SLE, 20 of their first-degree relatives and 20 healthy controls. The study also determined the systemic lupus erythematosus disease activity index (SLEDAI) score and proteinuria in SLE patients. The results revealed that miR-31 was lower expressed, while miR-21 was high expressed in SLE patients compared to their first-degree relatives and controls. MiR-31 was negatively correlated with SLEDAI and proteinuria in lupus patients, while miR-21 showed positive correlation with them. Also we found that there is a significant positive correlation between miR-31 and IL-2 in SLE patients, while miR-21 was negatively correlated with IL-2 level in patients. In conclusion, the study disclosed a significant association between miR-31 and miR-21 expression with IL-2 level in SLE patients. The regulatory biomarkers of miR-31 and miR-21 might have an impact on regulating IL-2 pathway expression and in turn on the activation of T lymphocytes in SLE.

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The clinical significance of decreased T cell interleukin‐2 production in systemic lupus erythematosus: Connecting historical dots

Cited by 10 publications

References 18 publications

Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood-Onset Systemic Lupus Erythematosus

Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood-Onset Systemic Lupus Erythematosus

Intrinsic Differences in Donor CD4 T Cell IL-2 Production Influence Severity of Parent-into-F1 Murine Lupus by Skewing the Immune Response Either toward Help for B Cells and a Sustained Autoantibody Response or toward Help for CD8 T Cells and a Downregulatory Th1 Response

The role of microRNA-31 and microRNA-21 as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients

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