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. 2018 Jan;191(1):50-59.
doi: 10.1111/cei.13050. Epub 2017 Oct 10.

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

D Mesquita Jr  1 , G Mastroianni Kirsztajn  2 , M F Franco  3 , L A Reis  2 , S F Perazzio  1 , F V Mesquita  1 , V da Silva Ferreira  1 , L E Coelho Andrade  1 , A W Silva de Souza  1
Affiliations

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

D Mesquita Jr et al. Clin Exp Immunol. 2018 Jan.

Abstract

The objective of this study was to evaluate the frequency of CD4+ 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 (Treg ) 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+ T cells were decreased in PBMC in LN compared with DC and HC (P = 0·0001). No differences were observed in urinary CD4+ 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 = 0·041). CD3+ and T-box 21 ( Tbet+) cells were found in glomeruli and interstitium of LN patients, while forkhead box protein 3 (FoxP3), retinoid-related orphan receptor gamma (ROR-γ) and GATA binding protein 3 (GATA-3) were present only in glomeruli. Th1 cells in PBMC were correlated negatively with urinary Th1 cells (Rho = -0·531; P = 0·028) and with Tbet in renal interstitium (Rho = -0·782; P = 0·004). 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+ T cells were not different between LN and DC.

Keywords: glomerulonephritis; helper T cells; lupus nephritis; regulatory T cells; systemic lupus erythematosus.

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Figures

Figure 1
Figure 1
Frequency of T helper type 17 (Th17) cells in patients with proliferative and non‐proliferative forms of lupus nephritis. Patients with proliferative lupus nephritis present a significantly lower frequency of Th17 cells in urine compared with patients with non‐proliferative lupus nephritis [3·85% (1·30–27·00) versus· 14·37% (4·42–57·80); P = 0·041].
Figure 2
Figure 2
Comparison between T cell subsets frequency in glomerular inflammatory infiltration in lupus nephritis. The glomerular expression of T box 21 (Tbet), GATA binding protein 3 (GATA3) and retinoid‐related orphan receptor gamma (ROR‐γ) was significantly higher than forkhead box protein 3 (FoxP3) in lupus nephritis (P < 0·0001 for each comparison). No significant differences were found among the expression of Tbet, GATA3 and ROR‐γ (P > 0·05).
Figure 3
Figure 3
Representative immunohistochemistry for glomerular expression of T box 21 (Tbet), GATA binding protein 3 (GATA3), retinoid‐related orphan receptor gamma (ROR‐γ) lupus nephritis at ×600 magnification. Cells stained in brown express Tbet (a), GATA3 (b), ROR‐γ (c) and forkhead box protein 3 (FoxP3) (d) (red arrows).
Figure 4
Figure 4
Representative immunohistochemistry for tubulointerstitial expression of T box 21 (Tbet), GATA binding protein 3 (GATA3), retinoid‐related orphan receptor gamma (ROR‐γ) and forkhead box protein 3 (FoxP3) in renal tissue from a patient with lupus nephritis. Immunohistochemistry in tubulointerstitial inflammatory infiltrate in the kidney from patients with lupus nephritis at ×600 magnification. Tbet (a) was the transcription factor observed more frequently in renal interstitium from patients with lupus nephritis compared with ROR‐γ (c) and FoxP3 (d) (red arrows). No expression of GATA3 was found in renal interstitium from patients with lupus nephritis (b).
Figure 5
Figure 5
Correlation between T helper type 1 (Th1) cells in peripheral blood mononuclear cells, urine and in renal tissue in lupus nephritis. A significant negative correlation was found between the frequency of peripheral blood Th1 cells and the expression of T box 21 (Tbet) in renal tissue (a) and between the frequency of peripheral blood Th1 cells and urinary Th1 cells (b).
Figure 6
Figure 6
CD4+ T cell subsets before and after 6 months of therapy for lupus nephritis. Relative frequency of peripheral regulatory T cells (Treg) cells (a), T helper type 17 (Th17) cells (b), Th1 cells (c) and Th2 cells (d) before and at 6 months therapy for lupus nephritis (LN). Only Th17 cells presented a significant increase in the frequency in peripheral blood at 6 months of therapy for LN (P = 0·008).
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