Abstract
Previous studies have shown that secretory IgA (sIgA) was critically involved in IgA nephropathy (IgAN) immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (N-sIgA). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients by immunohistochemistry, the expression levels in patients with positive sIgA deposition were higher than that with negative sIgA deposition. Human renal mesangial cells (HRMCs) were cultured in vitro, flow cytometry showed that P-sIgA bound HRMCs significantly better than N-sIgA. HRMCs were cultured in the presence of sIgA (400 μg/mL) for 24 h, compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB. TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients.
Highlights
IgA nephropathy (IgAN) is the most common primary glomerulonephritis in China and worldwide
To examine the deposition of SIgA in the renal tissue of IgAN patients, we used immunofluorescence to detect the deposition of IgA and secretory component (SC)
The results indicate that approximately one-third of IgAN patients have deposition of SIgA
Summary
IgA nephropathy (IgAN) is the most common primary glomerulonephritis in China and worldwide. The disease is characterized by deposition of IgA-based immune complexes in the glomerular mesangial areas which can be observed using immunofluorescence assays. It is believed that loss of IgA glycosylation, genetic factors and mucosal immunity are all involved in the pathogenesis of IgAN [4, 5]. A series of previous studies suggested that mucosal immune abnormalities, especially of sIgA, are involved in the development of IgAN. Multiple miRNAs are involved in regulation of sIgA-induced HRMC cytokine secretion and subsequent renal injury [9]. These studies suggest a key role for sIgA in IgAN
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