Abstract
IgA nephropathy (IgAN) is characterized by high serum IgA levels and IgA deposition in the renal mesangium. Recent research has indicated that pathogenic IgA may originate from affected tonsils, where present enhancement of IgA production by IgA class switching and immuno-activation. Tripterygium Wilfordii (TW) was found to be especially effective in IgAN by its’ immunosuppression effect. Given this background, we investigated the mechanisms underlying the role of TW in the generation of IgA and IgA class switching in tonsillar GCs of IgAN patients. Immunohistochemistry and RT-PCR revealed that the expression of thymic stromal lymphopoietin (TSLP) and IgA inducing cytokines were decreased in the tonsils of IgAN patients with TW treatment compared with those without treatment, followed by significantly decreased of IgA-bearing cells. The location of TSLP and IgA inducing cytokines in tonsillar tissue was confirmed by double immunofluorescence. Importantly, TW inhibit TSLP and IgA production in isolated FDC-associated clusters. Serum TSLP levels were decreased and correlated with IgA downregulation in the tonsils and serum of IgAN patients. These data indicated that TW may be involved in IgA production in the tonsils of IgAN patients, inhibiting IgA class switching in IgAN patients through the cooperative roles of AID, TGF-β1, BAFF, and APRIL, highlighting a promising strategy for therapeutic intervention in IgAN.
Highlights
Immunoglobulin A nephropathy (IgAN), the most common form of primary glomerulonephritis worldwide, is characterized by qualitative abnormalities in circulating IgA and IgA deposition in the renal mesangium [1, 2]
Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) revealed that the expression of thymic stromal lymphopoietin (TSLP) and IgA inducing cytokines were decreased in the tonsils of IgA nephropathy (IgAN) patients with Tripterygium Wilfordii (TW) treatment compared with those without treatment, followed by significantly decreased of IgA-bearing cells
We observed increased expression of TSLP in tonsillar germinal center (GC) of IgAN patients compared to IgAN patients with TW treatment and non-IgAN chronic tonsillitis, and there was a positive correlation between IgA and TSLP expression levels in tonsils (R = 0.768, and P < 0.05 for Spearman’s correlation; Figure 1D)
Summary
Immunoglobulin A nephropathy (IgAN), the most common form of primary glomerulonephritis worldwide, is characterized by qualitative abnormalities in circulating IgA and IgA deposition in the renal mesangium [1, 2]. Pathogenic IgA has been suggested to be crucial to the pathogenesis of IgAN, recent studies have suggested that tonsils are closely related to IgAN and that pathogenic IgA in IgAN is partly of tonsillar origin [3]. Chronic and recurrent tonsillitis are thought to play an important role in new onset and progression of IgAN [4]. The benefits of TW in patients with IgAN suggests that TW may be closely related to tonsillar IgA production. The mechanism of TW in tonsillar IgA production in IgAN is unknown
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