TLR7 in B cells promotes renal inflammation and Gd-IgA1 synthesis in IgA nephropathy

Abstract Background and Aims The IgA nephropathy (IgAN) is the most frequent primitive glomerulonephritis. In the last years, the role of mucosal immunity in IgAN, together with that of the gut microbiota in the activation of innate and adaptive immune cells, has gained importance. Particularly interesting is the role of the microbiota and intestinal immunity in IgAN. BAFF and APRIL can be produced by the intestinal epithelium, in response to signals triggered by TLRs once activated by the commensal bacteria present in the intestinal lumen, representing the link between microbiota and intestinal immunity. To date, even if hypothesized, this relationship in IgAN patients has not been investigated. Here, we studied the intestinal-renal axis connections analyzing levels of BAFF, April and intestinal-activated B cells in IgAN patients. Method Serum and fecal samples were collected from 44 IgAN patients, 22 non-IgA glomerulonephritides (controls) and 22 healthy subjects (HS) with similar clinical features. BAFF and APRIL serum levels were measured by ELISA assay. Metabolomic analysis of fecal microbiome was performed using Biochrom 30 series amino acid analyzer and gas-chromatography mass spectrometry/solid-phase microextraction (GC-MS/SPME) analysis. B cell subsets were investigated by FACS. Results IgAN patients had increased serum levels of BAFF cytokine compared to the control group of patients with non-IgA glomerulonephritis and compared with HS (p<0.0001and p=0.012, respectively). We found that serum BAFF levels positively correlated with the levels of 24h-proteinuria in IgAN patients (r2 = 0.2269, p <0.001). We correlated serum BAFF levels with fecal concentration of 5 different metabolites of 30 IgAN patients, which were previously investigated for the fecal microbiota. These organic compounds had been found at significantly higher levels in the feces of IgAN patients compared to HS. Serum BAFF levels positively correlated with the levels of fecal metabolites: 4-(1,1,3,3-tetramethylbutyl) phenol (r2 = 0.2882, p = 0.0027), p-tert-butyl-phenol (r2 = 0.386, p = 0.0003), methyl neopentyl phthalic acid (r2 = 0.3491, p =0.0007), hexadecyl ester benzoic acid (r2 = 0.2832, p =0.003) and furanone A (r2 = 0.1743, p = 0.024). Serum levels of APRIL were significantly increased in IgAN patients respect to control groups (4.49 ± 0.54 vs 2.27 ± 1 ng/ml, p=0.0014). We found a correlation between APRIL and serum creatinine (r2 = 0.159, p =0.04) and eGFR (r2 = 0.2395, p =0.0082), while no correlation was found between APRIL and fecal metabolite levels in IgAN patients. In addition, we found that subjects with IgAN have a significantly higher proportion of circulating Bregs, Memory B cells and IgA secreting-plasmablasts activated at the intestinal level (CCR9+INTB7+) compared to HS. Conclusion The results of our study showed for the first time an important correlation of serum levels of BAFF with intestinal microbiota in patients with IgAN, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in the IgAN patients. The intestinal-renal axis plays a crucial role in Berger's glomerulonephritis, whose complex pathogenesis may contribute several factors as genetics, pathogens and food.

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Increased frequency of PD-1hiCXCR5- T cells and B cells in patients with newly diagnosed IgA nephropathy

Scientific Reports ◽

10.1038/s41598-019-57324-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Xin Wang ◽

Tao Li ◽

Rui Si ◽

Jinyun Chen ◽

Zhihui Qu ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Iga Nephropathy ◽

Newly Diagnosed

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B cells and tertiary lymphoid organs in renal inflammation

Kidney International ◽

10.1038/sj.ki.5002734 ◽

2008 ◽

Vol 73 (5) ◽

pp. 533-537 ◽

Cited By ~ 53

Author(s):

S. Segerer ◽

D. Schlöndorff

Keyword(s):

B Cells ◽

Lymphoid Organs ◽

Renal Inflammation

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IgG antibody aggrevates the renal inflammation in an experimental model of IgA nephropathy in rats

Immunology Letters ◽

10.1016/s0165-2478(97)86272-4 ◽

1997 ◽

Vol 56 ◽

pp. 315

Author(s):

M.G.A. Van Dixhoom ◽

T. Sato ◽

Y. Muizert ◽

D.J. Van Gijlswijk-Janssen ◽

M.R. Daha

Keyword(s):

Iga Nephropathy ◽

Experimental Model ◽

Igg Antibody ◽

Renal Inflammation

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Different Pathological Roles of Toll-Like Receptor 9 on Mucosal B Cells and Dendritic Cells in Murine IgA Nephropathy

Clinical and Developmental Immunology ◽

10.1155/2011/819646 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 18

Author(s):

Tadahiro Kajiyama ◽

Yusuke Suzuki ◽

Masao Kihara ◽

Hitoshi Suzuki ◽

Satoshi Horikoshi ◽

...

Keyword(s):

B Cells ◽

Iga Nephropathy ◽

M2 Macrophage ◽

Disease Phenotype ◽

Toll Like Receptor ◽

Cell Type ◽

Weekly Administration ◽

Cpg Dna ◽

Serum Iga ◽

Sclerotic Lesions

Although pathogenesis of IgA nephropathy (IgAN) is still obscure, pathological contribution of mucosal immunity including production of nephritogenic IgA and IgA immune complex (IC) has been discussed. We have reported that mucosal toll-like receptor (TLR)-9 is involved in the pathogenesis of human and murine IgAN. However, cell-type expressing TLR9 in mucosa remains unclear. To address this, we nasally challenged cell-specific CpG DNA ((i): dendritic cell: (DC), (ii): B cell, (iii): both), known as ligand for TLR9, to IgAN prone mice and analyzed disease phenotype of each group. After 8 times of the weekly administration, every group showed deterioration of glomerular damage. However, CpG-A-group showed clear extension of mesangial proliferative lesions with increase of serum IgA-IgG2a IC and its glomerular depositions, while CpG-B-group showed extent of glomerular sclerotic lesions with increase of serum and glomerular IgA and M2 macrophage infiltration. Present results indicate that mucosal TLR9 on B cells and DC may differently contribute to the progression of this disease via induction of nephritogenic IgA or IgA-IgG IC, respectively. This picture is suggestive for the pathological difference between child and adult IgAN.

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Pathological Role of Tonsillar B Cells in IgA Nephropathy

Clinical and Developmental Immunology ◽

10.1155/2011/639074 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 21

Author(s):

Yusuke Suzuki ◽

Hitoshi Suzuki ◽

Junichiro Nakata ◽

Daisuke Sato ◽

Tadahiro Kajiyama ◽

...

Keyword(s):

B Cells ◽

Iga Nephropathy ◽

Pulse Therapy ◽

Experimental Information ◽

Specific Therapy ◽

Steroid Pulse ◽

Randomized Control ◽

Underlying Mechanisms ◽

Noninvasive Biomarkers

Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale.

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