Altered expression of signalling lymphocyte activation molecule receptors in T-cells from lupus nephritis patients—a potential biomarker of disease activity

Abstract Background and Aims Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC]. Methods The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR]. Results LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3−. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR. Conclusions LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC.

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Quantitative planar array screen of 1000 proteins uncovers novel urinary protein biomarkers of lupus nephritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-216312 ◽

2020 ◽

Vol 79 (10) ◽

pp. 1349-1361

Author(s):

Kamala Vanarsa ◽

Sanam Soomro ◽

Ting Zhang ◽

Briony Strachan ◽

Claudia Pedroza ◽

...

Keyword(s):

Growth Factor ◽

Lupus Nephritis ◽

Disease Activity ◽

Single Cell ◽

Rna Sequencing ◽

Lupus Erythematosus ◽

Transforming Growth Factor ◽

Sequencing Analysis ◽

Potential Biomarker ◽

Planar Array

ObjectiveThe goal of these studies is to discover novel urinary biomarkers of lupus nephritis (LN).MethodsUrine from systemic lupus erythematosus (SLE) patients was interrogated for 1000 proteins using a novel, quantitative planar protein microarray. Hits were validated in an independent SLE cohort with inactive, active non-renal (ANR) and active renal (AR) patients, in a cohort with concurrent renal biopsies, and in a longitudinal cohort. Single-cell renal RNA sequencing data from LN kidneys were examined to deduce the cellular origin of each biomarker.ResultsScreening of 1000 proteins revealed 64 proteins to be significantly elevated in SLE urine, of which 17 were ELISA validated in independent cohorts. Urine Angptl4 (area under the curve (AUC)=0.96), L-selectin (AUC=0.86), TPP1 (AUC=0.84), transforming growth factor-β1 (TGFβ1) (AUC=0.78), thrombospondin-1 (AUC=0.73), FOLR2 (AUC=0.72), platelet-derived growth factor receptor-β (AUC=0.67) and PRX2 (AUC=0.65) distinguished AR from ANR SLE, outperforming anti-dsDNA, C3 and C4, in terms of specificity, sensitivity and positive predictive value. In multivariate regression analysis, urine Angptl4, L-selectin, TPP1 and TGFβ1 were highly associated with disease activity, even after correction for demographic variables. In SLE patients with serial follow-up, urine L-selectin (followed by urine Angptl4 and TGFβ1) were best at tracking concurrent or pending disease flares. Importantly, several proteins elevated in LN urine were also expressed within the kidneys in LN, either within resident renal cells or infiltrating immune cells, based on single-cell RNA sequencing analysis.ConclusionUnbiased planar array screening of 1000 proteins has led to the discovery of urine Angptl4, L-selectin and TGFβ1 as potential biomarker candidates for tracking disease activity in LN.

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AB0020 Expression levels of signaling lymphocyte activation molecule family 6 (SLAMF6) on circulating follicular helper T cells are associated with disease activity in systemic lupus erythematosus

10.1136/annrheumdis-2017-eular.6078 ◽

2017 ◽

Author(s):

SE Kang ◽

SJ Lee ◽

DJ Go ◽

HM Kwon ◽

EY Ahn ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Disease Activity ◽

Lupus Erythematosus ◽

Lymphocyte Activation ◽

Helper T Cells ◽

Follicular Helper T Cells ◽

Systemic Lupus ◽

Expression Levels ◽

Follicular Helper

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CD107a+ (LAMP-1) Cytotoxic CD8+ T-Cells in Lupus Nephritis Patients

Frontiers in Medicine ◽

10.3389/fmed.2021.556776 ◽

2021 ◽

Vol 8 ◽

Author(s):

Anika Wiechmann ◽

Benjamin Wilde ◽

Bartosz Tyczynski ◽

Kerstin Amann ◽

Wayel H. Abdulahad ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Nephritis ◽

Cd8 T Cells ◽

Lupus Erythematosus ◽

Inactive Disease ◽

Healthy Controls ◽

Systemic Lupus ◽

Altered Expression

Cytotoxic CD8+ T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8+ T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients (n = 31) and healthy controls (n = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8+ and C107a+ cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a+ on CD8+ T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ± 18.5% vs. 47.9 ± 15.0%, p = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a+CD8+ T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a+CD8+ T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a+ was significantly correlated with proteinuria. These results demonstrate that CD8+ T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a+CD8+ suggests a role in the pathogenesis of lupus nephritis.

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Urine Monocyte Chemoattractant Protein-1 and Lupus Nephritis Disease Activity: Preliminary Report of a Prospective Longitudinal Study

Autoimmune Diseases ◽

10.1155/2015/962046 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Sabah Alharazy ◽

Norella C. T. Kong ◽

Marlyn Mohd ◽

Shamsul A. Shah ◽

Arbaiyah Ba’in ◽

...

Keyword(s):

Longitudinal Study ◽

Lupus Nephritis ◽

Disease Activity ◽

Multiple Logistic Regression Analysis ◽

Prospective Longitudinal Study ◽

Monocyte Chemoattractant Protein 1 ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Potential Biomarker ◽

Prospective Longitudinal

Objective. This longitudinal study aimed to determine the urine monocyte chemoattractant protein-1 (uMCP-1) levels in patients with biopsy-proven lupus nephritis (LN) at various stages of renal disease activity and to compare them to current standard markers.Methods. Patients with LN—active or inactive—had their uMCP-1 levels and standard disease activity markers measured at baseline and 2 and 4 months. Urinary parameters, renal function test, serological markers, and renal SLE disease activity index-2K (renal SLEDAI-2K) were analyzed to determine their associations with uMCP-1.Results. A hundred patients completed the study. At each visit, uMCP-1 levels (pg/mg creatinine) were significantly higher in the active group especially with relapses and were significantly associated with proteinuria and renal SLEDAI-2K. Receiver operating characteristic (ROC) curves showed that uMCP-1 was a potential biomarker for LN. Whereas multiple logistic regression analysis showed that only proteinuria and serum albumin and not uMCP-1 were independent predictors of LN activity.Conclusion. uMCP-1 was increased in active LN. Although uMCP-1 was not an independent predictor for LN activity, it could serve as an adjunctive marker when the clinical diagnosis of LN especially early relapse remains uncertain. Larger and longer studies are indicated.

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A2.01 Increased soluble CD72 in systemic lupus erythematosus: A potential biomarker for disease activity and lupus nephritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-209124.37 ◽

2016 ◽

Vol 75 (Suppl 1) ◽

pp. A15.3-A16

Author(s):

Z Vadasz ◽

E Toubi

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Disease Activity ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Potential Biomarker

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CD107a+ (LAMP-1) cytotoxic CD8+ T-cells in lupus nephritis patients

10.21203/rs.2.24347/v1 ◽

2020 ◽

Author(s):

Anika Wiechmann ◽

Benjamin Wilde ◽

Kerstin Amann ◽

Wayel H. Abdulahad ◽

Andreas Kribben ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Nephritis ◽

Cd8 T Cells ◽

Lupus Erythematosus ◽

Inactive Disease ◽

Healthy Controls ◽

Systemic Lupus ◽

Altered Expression

Abstract Background: Cytotoxic CD8 + T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8 + T-cells in SLE-patients in particular with lupus nephritis. Methods: Peripheral blood of SLE-patients (n=31) and healthy controls (n=21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8 + and C107a + cells by immunohistochemistry. Results: The percentages of CD107a + on CD8 + T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ±18.5 % vs. 47.9 ± 15.0 %, p=0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a + CD8 + T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a + CD8 + T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a + was significantly correlated with proteinuria. Conclusion: These results demonstrate that CD8 + T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a + CD8 + suggests a role in the pathogenesis of lupus nephritis.

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