Imbalance towards Th1 pathway predominance in purpura nephritis with proteinuria

Abstract

Although recent reports suggest a possible role for an imbalance in Th1 and Th2 proinflammatory cytokines in the development and progression of glomerulonephritis, there is little information on Th1 or Th2 predominance in Henoch-Schönlein purpura nephritis (HSPN). Since T-bet and GATA-3 are transcriptional factors that regulate the differentiation of helper T lymphocytes into Th1 and Th2, we examined the relative mRNA expression of T-bet and GATA-3 in the urinary sediment of children with proteinuric HSPN by real-time quantitative PCR. Eight consecutive patients with proteinuric HSPN (4 with grade IIIa and 4 with grade IIIb according to the International Study of Kidney Disease in Children criteria) and 20 healthy subjects were enrolled in this study. The relative expression level of T-bet was significantly higher in the urinary sediment of patients with HSPN at presentation than in that of the healthy controls (p = 0.021), while the relative expression of GATA-3 was significantly lower in the urinary sediment of patients than in that of controls (p = 0.002). Urinary mRNA expression of T-bet correlated with the urinary protein/creatinine ratio (r = 0.608, p = 0.013), and correlated inversely with serum level of total protein (r = -0.574, p = 0.020). Moreover, a significantly increased intensity of T-bet immunostaining was observed in the glomeruli in the biopsy specimen of all study patients. All patients received immunosuppressive therapy. Repeat measurements of urinary mRNA expression of T-bet and GATA-3 after treatment revealed that the expression of T-bet in patients had significantly decreased relative to the baseline (p = 0.003), while the expression of GATA-3 remained static. In a patient subjected to a post-treatment renal biopsy, the increased intensity of immunostaining of T-bet had clearly diminished following immunosuppressive treatment, in accordance with a significant decrease in urinary mRNA expression of T-bet. These observations suggest that patients with proteinuric HSPN demonstrate increased T-bet and depressed GATA-3 expression in the urinary sediment, indicating a possible shift in Th1/Th2 balance towards Th1 predominance.

Henoch–Schönlein purpura in 535 Chinese children: clinical features and risk factors for renal involvement

“…15 In the present study, T-cell, B-cell and NK cell percentages and ratios in peripheral blood and serum concentrations of immunoglobulins A, M and G were measured, but no significant differences were found between HSP patients with or without nephritis. However, immune function was only tested at one timepoint; dynamic monitoring may be required to clarify the roles of the cellular and humoral immune systems in HSPN pathogenesis.…”

Urinary Fractalkine and Monocyte Chemoattractant Protein-1 as Possible Predictors of Disease Activity of Childhood Glomerulonephritis

“…Thus, a non-invasive monitoring method is desirable in patients with kidney disease, especially pediatric-onset GN. Recently, it has been reported that the gene expression of functional molecules, such as transcriptional factors and proinflammatory cytokines/chemokines, in urinary sediment reflects pathogenesis and disease activity in patients with lupus nephritis (LN), IgA nephropathy (IgAN) and purpura nephritis (PN), and could be used for non-invasive monitoring of disease activity and response to treatment, without the potential demerits of invasive renal biopsy (Chan et al 2003;Wang and Szeto 2007;Tsuruga et al 2010Tsuruga et al , 2011. However, measurement of messenger RNA in urinary sediment is not always possible for routine examination because of RNA instability (Szeto et al 2012).…”

Expressions of mRNA for innate immunity‐associated functional molecules in urinary sediment in immunoglobulin A nephropathy

“…A whole‐stream, early morning, urine sample at the time of renal biopsy was collected for the gene expression study . Briefly, the urine samples were centrifuged at 1650 g for 30 min.…”

“…It has recently been reported that quantification of messenger RNA expression of certain target genes in urinary sediment by reverse transcription became possible, and real‐time quantitative polymerase chain reaction (RT‐qPCR) may be a valuable noninvasive method for studying kidney diseases . We previously examined mRNA expression of transcriptional factors for the differentiation of helper T lymphocytes toward Th1, T‐bet and Th2, GATA‐3 in urinary sediment of children with IgAN and purpura nephritis (PN), and found that newly diagnosed cases showed a higher expression of T‐bet in urinary sediment compared to controls, and that this higher expression was associated with positive staining of T‐bet protein in renal biopsied tissue .…”

“…It has recently been reported that quantification of messenger RNA expression of certain target genes in urinary sediment by reverse transcription became possible, and real‐time quantitative polymerase chain reaction (RT‐qPCR) may be a valuable noninvasive method for studying kidney diseases . We previously examined mRNA expression of transcriptional factors for the differentiation of helper T lymphocytes toward Th1, T‐bet and Th2, GATA‐3 in urinary sediment of children with IgAN and purpura nephritis (PN), and found that newly diagnosed cases showed a higher expression of T‐bet in urinary sediment compared to controls, and that this higher expression was associated with positive staining of T‐bet protein in renal biopsied tissue . In an experimental setting, we also examined the TLR3 signalling cascades treated with polyinosinic‐polycytidylic acid (poly IC), a synthetic analogue of viral dsRNA, that makes ‘pseudoviral’ infection in cultured human mesangial cells (MCs), and found that the activation of mesangial TLR3 upregulated the expressions of monocyte/macrophage and lymphocyte chemoattractants: CC ligand chemokine 5 (CCL5), fractalkine /CX3CL1, interferon (IFN)‐γ‐induced protein 10 (IP‐10), and monocyte chemoattractant protein‐1 (MCP‐1), in cultured human MCs .…”