CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients

Enghard, Philipp; Humrich, Jens Y; Rudolph, Birgit; Rosenberger, Stefan; Biesen, Robert; Kuhn, Annegret; Manz, Rudolf A.; Hiepe, Falk; Radbruch, Andreas; Gr, Burgio; Riemekasten, Gabriela

doi:10.1002/art.24136

Cited by 135 publications

(135 citation statements)

References 24 publications

(24 reference statements)

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“…In this study, we could demonstrate high intrarenal mRNA expression of CXCR3 and its ligand IP10/ CXCL10 as well as CXCR3 bearing Th cells infiltrating the inflamed kidneys. These findings are in line with recently published data (43) and suggest that CXCR3-mediated renal T cell trafficking is not only important in murine, but also in human lupus nephritis.…”

Section: Discussionsupporting

confidence: 92%

CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis

Steinmetz¹,

Turner²,

Paust³

et al. 2009

The Journal of Immunology

146

126

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Infiltration of T cells into the kidney is a typical feature of human and experimental lupus nephritis that contributes to renal tissue injury. The chemokine receptor CXCR3 is highly expressed on Th1 cells and is supposed to be crucial for their trafficking into inflamed tissues. In this study, we explored the functional role of CXCR3 using the MRL/MpJ-Faslpr (MRL/lpr) mouse model of systemic lupus erythematosus that closely resembles the human disease. CXCR3−/− mice were generated and backcrossed into the MRL/lpr background. Analysis of 20-wk-old CXCR3−/− MRL/lpr mice showed amelioration of nephritis with reduced glomerular tissue damage and decreased albuminuria and T cell recruitment. Most importantly, not only the numbers of renal IFN-γ-producing Th1 cells, but also of IL-17-producing Th17 cells were significantly reduced. Unlike in inflamed kidneys, there was no reduction in the numbers of IFN-γ- or IL-17-producing T cells in spleens, lymph nodes, or the small intestine of MRL/lpr CXCR3−/− mice. This observation suggests impaired trafficking of effector T cells to injured target organs, rather than the inability of CXCR3−/− mice to mount efficient Th1 and Th17 immune responses. These findings show a crucial role for CXCR3 in the development of experimental lupus nephritis by directing pathogenic effector T cells into the kidney. For the first time, we demonstrate a beneficial effect of CXCR3 deficiency through attenuation of both the Th1 and the newly defined Th17 immune response. Our data therefore identify the chemokine receptor CXCR3 as a promising therapeutic target in lupus nephritis.

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Section: Discussionsupporting

confidence: 92%

CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis

Steinmetz¹,

Turner²,

Paust³

et al. 2009

The Journal of Immunology

146

126

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“…The number of LN patients presenting class V was indeed too low in this study to draw definite conclusions about this issue. Some studies have shown that urine samples from patients with LN contain increased absolute numbers of T cells per ml and they can be detected and quantified by flow cytometry analysis [12,14,26]. We could not find any specific pattern of urinary CD4…”

Section: Discussioncontrasting

confidence: 57%

“…1 T cells in urine have been reported to be useful to detect active disease, response to treatment and to be a prognostic marker in LN, indicating a worse clinical outcome and lower treatment response in LN patients with persistent or increasing urinary CD4 1 T cells, despite therapy [12,13]. In addition, the number of CD8 1 T cells in urine seem to be a good marker for assessment of disease activity and remission in LN [14].…”

Section: Cxcr3mentioning

confidence: 99%

“…In an effort to identify possible associations between cellular or molecular alterations in the urine with clinical parameters of LN a number of urinary biomarkers have been evaluated in recent years, among which urinary T cell counts are promising surrogate markers for active LN. In fact, patients with active LN present increased absolute numbers of CD4 1 and CD8 1 T cells in the urine [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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CD4+ T helper cells and regulatory T cells in active lupus nephritis: an imbalance towards a predominant Th1 response?

Mesquita

Kirsztajn

Franco

et al. 2017

Clinical and Experimental Immunology

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SummaryThe objective of this study was to evaluate the frequency of CD4 1 T cell subsets in peripheral blood mononuclear cells (PBMC), urine and renal tissue from patients with lupus nephritis (LN). PBMC and urinary cells were collected from 17 patients with active LN, 20 disease controls (DC) with primary glomerulonephritis and 10 healthy controls (HC) and were analysed by flow cytometry with markers for T helper type 1 (Th1), Th2, Th17 and regulatory T cells (T reg ) cells. T cell subsets were assessed by immunohistochemistry from LN biopsy specimens from 12 LN patients. T cell subtypes in PBMC were re-evaluated at 6 months of therapy. CD4 1 T cells were decreased in PBMC in LN compared with DC and HC (P 5 0Á0001). No differences were observed in urinary CD4 1 T cell subsets between LN and DC. The frequency of urinary Th17 cells was higher in patients with non-proliferative than in proliferative LN (P 5 0Á041). CD3 1 and T-box 21 (T 1 bet ) cells were found in glomeruli and interstitium of LN patients, while forkhead box protein 3 (FoxP3), retinoid-related orphan receptor gamma (ROR-g) and GATA binding protein 3 (GATA-3) were present only in glomeruli. Th1 cells in PBMC were correlated negatively with urinary Th1 cells (Rho 5 -0Á531; P 5 0Á028) and with T bet in renal interstitium (Rho 5 -0Á782; P 5 0Á004). At 6 months, LN patients showed an increase in Th17 cells in PBMC. In conclusion, the inverse association between Th1 cells from PBMC and urinary/renal tissue indicate a role for Th1 in LN pathophysiology. Urinary Th17 cells were associated with less severe LN, and Th17 increased in PBMC during therapy. Urinary CD4 1 T cells were not different between LN and DC.

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“…30 A role of CXCR3 in Treg trafficking has recently been suggested in the EAE model and ConA-induced hepatitis. 31,32 The recruitment of CXCR3 + T cells into the kidney was shown in human and experimental GN, 33,34 and subsequent studies showed that CXCR3 mediates T effector cell recruitment and tissue injury in experimental models of crescentic GN. 35,36 These studies show the potential beneficial effect of nonselective CXCR3 blockade in crescentic GN.…”

Section: Discussionmentioning

confidence: 99%

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

Paust¹,

Riedel²,

Krebs³

et al. 2015

JASN

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Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the T H 1-associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA-associated crescentic GN and colocalize with CXCR3 + effector T cells.

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CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients

Cited by 135 publications

References 24 publications

CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis

CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis

CD4+ T helper cells and regulatory T cells in active lupus nephritis: an imbalance towards a predominant Th1 response?

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

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