Correlation of clonal T cell expansion with disease activity in systemic lupus erythematosus

T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) has been found to play important roles in systemic lupus erythematosus (SLE), however, whether Tim-3 is involved in apoptosis of NK cells in SLE remains unknown. The proportion of CD3−CD56+ NK cells and the percentage of AnnexinV+ NK cells were analyzed by flow cytometry in SLE patients and healthy controls. Tim-3 expression on NK cells was also evaluated by flow cytometry. We firstly observed a decreased proportion of NK cells and an increased proportion of apoptotic NK cells in SLE patients. The proportion of apoptotic NK cells was positively correlated with anti-dsDNA and SLEDAI. Tim-3 expression on NK cells was up-regulated in SLE patients. Further analysis showed that Tim-3 expression on NK cells was negatively correlated with the proportion of apoptotic NK cells, anti-dsDNA and SLEDAI, while positively correlated with the proportion of NK cells. The present results suggest that Tim-3 might play roles in SLE by regulating the apoptosis of NK cells and Tim-3 might serve as a potential target for the treatment of SLE.

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Associations of site-specific CD4+-T-cell hypomethylation within CD40-ligand promotor and enhancer regions with disease activity of women with systemic lupus erythematosus

Lupus ◽

10.1177/0961203320965690 ◽

2020 ◽

Vol 30 (1) ◽

pp. 45-51

Author(s):

Stefan Vordenbäumen ◽

Anna Rosenbaum ◽

Claudia Gebhard ◽

Johanna Raithel ◽

Alexander Sokolowski ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Activity Index ◽

Disease Activity Index ◽

Cd40 Ligand ◽

Systemic Lupus ◽

Site Specific

Objective To comprehensively assess associations of site-specific CD4+-T-cell hypomethylation of the CD40-Ligand gene ( CD40L) with disease activity of women with systemic lupus erythematosus (SLE). Methods CpG-sites within the DNA of the promotor and two enhancer regions (n = 22) of CD40L were identified and numbered consecutively. The rate of methylated DNA in isolated CD4+-T-cells of women with SLE were quantified for each methylation site by MALDI-TOF. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Associations of site-specific methylation rates with the SLEDAI scores were assessed by linear regression modelling. P values were adjusted according to Bonferroni-Holm as indicated. Results 60 female SLE patients participated in the study (age 45.7 ± 11.1 years, disease duration 17.0 ± 8.3 years). Significant associations to the SLEDAI were noted for CpG22 hypomethylation of the promotor (β = −40.1, p = 0.017, adjusted p = 0.027), trends were noted for CpG17 hypomethylation of the promotor (β = −30.5, p = 0.032, adjusted p = 0.6), and for CpG11 hypermethylation of the second enhancer (β = 15.0, p = 0.046, adjusted p = 0.8). Conclusion Site-specific hypomethylation of the CD40L promotor in CD4+-T-cells show associations with disease activity in female SLE patients.

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CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.675250 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nur Diyana Mohd Shukri ◽

Aziz Farah Izati ◽

Wan Syamimee Wan Ghazali ◽

Che Maraina Che Hussin ◽

Kah Keng Wong

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Lymphocyte Subpopulations ◽

Gene Set Enrichment Analysis ◽

T Cell Subsets ◽

Healthy Controls ◽

Systemic Lupus

The receptors for IL-35, IL-12Rβ2 and gp130, have been implicated in the inflammatory pathophysiology of autoimmune diseases. In this study, we set out to investigate the serum IL-35 levels and the surface levels of IL-12Rβ2 and gp130 in CD3+CD4+, CD3+CD4─ and CD3─CD4─ lymphocyte subpopulations in systemic lupus erythematosus (SLE) patients (n=50) versus healthy controls (n=50). The potential T cell subsets associated with gp130 transcript (i.e. IL6ST) expression in CD4+ T cells of SLE patients was also examined in publicly-available gene expression profiling (GEP) datasets. Here, we report that serum IL-35 levels were significantly higher in SLE patients than healthy controls (p=0.038) but it was not associated with SLEDAI-2K scores. The proportions of IL-12Rβ2+ and gp130+ cells in SLE patients did not differ significantly with those of healthy controls in all lymphocyte subpopulations investigated. Essentially, higher SLEDAI-2K scores were positively correlated with increased proportion of gp130+ cells, but not IL-12Rβ2+ cells, on CD3+CD4+ T cells (r=0.425, p=0.002, q=0.016). Gene Set Enrichment Analysis (GSEA) of a GEP dataset of CD4+ T cells isolated from SLE patients (n=8; GSE4588) showed that IL6ST expression was positively associated with genes upregulated in CD4+ T cells vs myeloid or B cells (q<0.001). In an independent GEP dataset of CD4+ T cells isolated from SLE patients (n=9; GSE1057), IL6ST expression was induced upon anti-CD3 stimulation, and that Treg, TCM and CCR7+ T cells gene sets were significantly enriched (q<0.05) by genes highly correlated with IL6ST expression (n=92 genes; r>0.75 with IL6ST expression) upon anti-CD3 stimulation in these SLE patients. In conclusion, gp130 signaling in CD3+CD4+ T cell subsets may contribute to increased disease activity in SLE patients, and it represents a promising therapeutic target for inhibition in the disease.

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BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in Systemic Lupus Erythematosus

10.1101/2021.07.07.21260124 ◽

2021 ◽

Author(s):

Quentin Moyon ◽

Delphine Sterlin ◽

Makoto Miyara ◽

Francois Anna ◽

Alexis Mathian ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cell ◽

Antibody Response ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Serum Levels ◽

T Cell Response ◽

Inactive Disease ◽

Systemic Lupus

Objectives: Our aims were to evaluate Systemic Lupus Erythematosus (SLE) disease activity and SARS-CoV-2 specific immune responses after BNT162b2 vaccination. Methods: In this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine, until day 15 after the second dose in 126 SLE patients. SARS-CoV-2 antibody responses were measured against wild-type spike antigen while serum-neutralizing activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T-cell responses were quantified by Interferon (IFN)-gamma; release assay after the second dose. Results: BNT162b2 was well tolerated and no statistically significant variations of BILAG and SLEDAI scores were observed throughout the study in SLE patients with active and inactive disease at baseline. Mycophenolate Mofetil (MMF) and Methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody-response (beta=-78; p=0.007, beta=-122; p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total IgG serum levels, naive B cell frequencies (beta=2; p=0.018, beta=2.5; p=0.003) and SARS-CoV-2-specific T cell response (r=0.462; p=0.003). In responders, serum neutralization activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients. Conclusion: MMF, MTX and poor baseline humoral immune status, particularly: low naive B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating SLE patients who might need adapted vaccine regimens and follow-up.

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Low-density granulocytes activate T cells and demonstrate a non-suppressive role in systemic lupus erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214620 ◽

2019 ◽

Vol 78 (7) ◽

pp. 957-966 ◽

Cited By ~ 25

Author(s):

Saifur Rahman ◽

Divya Sagar ◽

Richard N Hanna ◽

Yaima L Lightfoot ◽

Pragnesh Mistry ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Cytokine Production ◽

Low Density ◽

Dependent Manner ◽

Systemic Lupus ◽

Lymphocyte Ratio

ObjectivesThe presence of proinflammatory low-density granulocytes (LDG) has been demonstrated in autoimmune and infectious diseases. Recently, regulatory neutrophilic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) were identified in systemic lupus erythematosus (SLE). Because LDG and PMN-MDSC share a similar phenotype with contrasting functional effects, we explored these cells in a cohort of patients with SLE.MethodsLDG and normal-density granulocytes (NDG) were isolated from fresh blood of healthy donors (HD) and patients with SLE. Associations between LDG and clinical manifestations were analysed. Multicolor flow cytometry and confocal imaging were performed to immunophenotype the cells. The ability of LDG and NDG to suppress T cell function and induce cytokine production was quantified.ResultsLDG prevalence was elevated in SLE versus HD, associated with the interferon (IFN) 21-gene signature and disease activity. Also, the LDG-to-lymphocyte ratio associated better with SLE disease activity index than neutrophil-to-lymphocyte ratio. SLE LDG exhibited significantly heightened surface expression of various activation markers and also of lectin-like oxidised low-density lipoprotein receptor-1, previously described to be associated with PMN-MDSC. Supernatants from SLE LDG did not restrict HD CD4+ T cell proliferation in an arginase-dependent manner, suggesting LDG are not immunosuppressive. SLE LDG supernatants induced proinflammatory cytokine production (IFN gamma, tumour necrosis factor alpha and lymphotoxin alpha) from CD4+ T cells.ConclusionsBased on our results, SLE LDG display an activated phenotype, exert proinflammatory effects on T cells and do not exhibit MDSC function. These results support the concept that LDG represent a distinct proinflammatory subset in SLE with pathogenic potential, at least in part, through their ability to activate type 1 helper responses.

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A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus

Clinical Immunology ◽

10.1016/j.clim.2013.12.002 ◽

2014 ◽

Vol 150 (2) ◽

pp. 192-200 ◽

Cited By ~ 20

Author(s):

Alexandros P. Grammatikos ◽

Vasileios C. Kyttaris ◽

Katalin Kis-Toth ◽

Lisa M. Fitzgerald ◽

Amy Devlin ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Cell Gene Expression ◽

Cell Gene

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Elevated serum autoantibodies against co-inhibitory PD-1 facilitate T cell proliferation and correlate with disease activity in new-onset systemic lupus erythematosus patients

Arthritis Research & Therapy ◽

10.1186/s13075-017-1258-4 ◽

2017 ◽

Vol 19 (1) ◽

Cited By ~ 9

Author(s):

Hui Shi ◽

Junna Ye ◽

Jialin Teng ◽

Yufeng Yin ◽

Qiongyi Hu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Cell Proliferation ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Elevated Serum ◽

T Cell Proliferation ◽

Systemic Lupus ◽

Onset Systemic Lupus Erythematosus ◽

New Onset

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Rapamycin Reduces Disease Activity and Normalizes T Cell Activation-Induced Calcium Fluxing in Patients With Systemic Lupus Erythematosus

Yearbook of Medicine ◽

10.1016/s0084-3873(08)70013-0 ◽

2007 ◽

Vol 2007 ◽

pp. 18-20

Author(s):

S.M. Berney

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cell ◽

Disease Activity ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Systemic Lupus

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Serum Levels of T Cell Immunoglobulin and Mucin-Domain Containing Molecule 3 in Patients with Systemic Lupus Erythematosus

Journal of Clinical Medicine ◽

10.3390/jcm9113563 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3563

Author(s):

Tomoyuki Asano ◽

Naoki Matsuoka ◽

Yuya Fujita ◽

Haruki Matsumoto ◽

Jumpei Temmoku ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cell ◽

Renal Disease ◽

Disease Activity ◽

Lupus Erythematosus ◽

Serum Levels ◽

Organ Damage ◽

Enzyme Linked Immunosorbent Assay ◽

Clinical Parameters ◽

Systemic Lupus

Objective: T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3) is implicated in the development of various autoimmune diseases. We aimed to investigate the levels of soluble TIM-3 (sTIM-3) and their associations between clinical parameters in patients with systemic lupus erythematosus (SLE). Methods: Serum samples were collected from 65 patients with SLE and 35 age-matched healthy controls (HCs). The SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI) were used to assess SLE disease activity and SLE-related organ damage. British Isles Lupus Assessment Group (BILAG)-2004 index was also used to assess SLE disease activity. Soluble TIM-3 (sTIM-3) in sera from patients with SLE and HCs were evaluated by enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical parameters of SLE including SLE disease activity. Results: Serum sTIM-3 levels in patients with SLE (median 2123 pg/mL (interquartile range (IQR), 229–7235)) were significantly higher than those in HCs (1363 pg/mL; IQR, 1097–1673; p = 0.0015). Serum levels of sTIM-3 were correlated with disease activity of SLE using the SLEDAI-2K score (p < 0.001, r = 0.53). The serum sTIM-3 levels in SLE patients with active renal disease (BILAG renal index A-B) were significantly higher than those without the active renal disease (BILAG renal index C–E). However, no significant difference was observed in serum sTIM-3 levels between SLE patients with and without active involvement in other organs (BILAG index). Serum sTIM-3 levels were significantly elevated in SLE patients with organ damage (2710 pg/mL; IQR, 256–7235) compared to those without organ damage (1532 pg/mL; IQR, 228–5274), as assessed by the SDI (p = 0.0102). Conclusions: Circulating sTIM-3 levels are elevated in SLE patients, and serum sTIM-3 levels are associated with SLE disease activity and SLE-related organ damage. The data indicate a possible link between the TIM-3/Gal-9 pathway and SLE clinical phenotypes, and further investigation of the TIM-3 pathway in SLE pathophysiology is warranted.

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