High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients

Abstract

Background Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis. The role of the microbiota and mucosal immunity in the pathogenesis of IgAN remains a key element. To date, the hypothetical relationship between commensal bacteria, elevated tumour necrosis factor (TNF) superfamily member 13 [also known as B-cell activating factor (BAFF)] levels, perturbed homoeostasis of intestinal-activated B cells and intestinal IgA class switch has not been clearly shown in IgAN patients. Methods We studied the intestinal–renal axis connections, analysing levels of BAFF, TNF ligand superfamily member 13 (APRIL) and intestinal-activated B cells in IgAN patients, healthy subjects (HSs) and patients with non-IgA glomerulonephritides. Results IgAN patients had increased serum levels of BAFF cytokine, correlating with higher amounts of five specific microbiota metabolites, and high APRIL cytokine serum levels. We also found that subjects with IgAN have a higher level of circulating gut-homing (CCR9+ β7 integrin+) regultory B cells, memory B cells and IgA+ memory B cells compared with HSs. Finally, we found that IgAN patients had high levels of both total plasmablasts (PBs) and intestinal-homing PBs. Interestingly, PBs significantly increased in IgAN but not in patients with other glomerulonephritides. Conclusions Our results demonstrate a significant difference in the amount of intestinal-activated B lymphocytes between IgAN patients and HSs, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in IgAN. The intestinal–renal axis plays a crucial role in IgAN and several factors may contribute to its complex pathogenesis and provide an important area of research for novel targeted therapies to modulate progression of the disease.

Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism modulated by viral and bacterial RNA

“…This kind of mechanism, driven by the epigenetic silencing of VTRNA2-1, may therefore explain both the high levels of IL-6, and infection involvement in the disease, and recent data showing microbiota involvment in IgAN (9) (41) (42). Our hypothesis is also supported by studies showing that synthetic double-stranded RNA poly(I:C) stimulation promotes IgA class-switch recombination and BAFF productions in tonsil mononuclear cells via the TLR3 pathway(43).…”

“…IgAN patients had greater BAFF cytokine blood levels, which were linked to higher levels of five microbiota metabolites, and high APRIL cytokine serum levels. In comparison to HS, IgAN individuals had a larger number of circulating gut-homing (CCR9 β7 integrin) regulatory B cells, memory B cells, and IgA memory B cells(9).…”

Identifying Therapeutic Strategies in IgA Nephropathy through Comprehensive Transcriptomic Characterization

“…The latter finding is interesting considering that plasmablasts, the precursor cells of plasma cells, were found to be elevated in serum of IgAN patients, a finding distinct from other glomerulonephritis. 40 Circulating plasmablasts have been found to correlate with level of proteinuria in IgAN patients 41 and these findings suggests possible utility of plasma cell targeting therapies in IgAN.…”

Rifaximin as a Potential Treatment for IgA Nephropathy in a Humanized Mice Model

“…The intestinal-activated B cells play a central role in pathogens and mucosal inflammatory diseases [18,19]. Epithelium-derived BAFF is the major modulator of B cell development and it has a key role in IgA class switching and plasma cell survival in the MALT.…”