O-Glycosylation of Serum IgA1 Antibodies against Mucosal and Systemic Antigens in IgA Nephropathy

Smith, Alice C.; Molyneux, Karen; Feehally, John; Barratt, Jonathan

doi:10.1681/asn.2006060658

Cited by 112 publications

(76 citation statements)

References 30 publications

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“…These in silico predictions coupled with previous in vitro data demonstrating modulation of IgA1 O-galactosylation by Th2 cytokines and IL-6 36,37 , as well as our previous observation that IgA1 O-galactosylation varies depending on the site of antigen encounter and B cell activation 38 , are consistent with an effect of the H1 haplotype on transcriptional control of C1GALT1 particularly in IgA1-committed B cells.…”

Section: Discussionsupporting

confidence: 87%

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Gale

Molyneux

Wimbury

et al. 2017

JASN

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112

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IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O-glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in Caucasian and Chinese populations.Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. Caucasian IgAN patients exhibited significantly higher Gd-IgA1 levels than Chinese patients. Among individuals without IgAN, Gd-IgA1 levels were not correlated with kidney function. Gd-IgA1 level heritability (h ). This association was replicated in GWAS of separate cohorts comprising: 308 UK patients with membranous glomerulonephritis (p<10

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Section: Discussionsupporting

confidence: 87%

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Gale

Molyneux

Wimbury

et al. 2017

JASN

Self Cite

112

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“…After tonsillar stimulation, patients with IgAN, especially those suffering from macroscopic hematuria, had high levels of serum SIgA and elevated salivary levels of SIgA [28,29]. High sera SIgA concentrations correlated with macroscopic hematuria in IgAN [26,30]. Deposition of SIgA in the mesangium was also observed in patients with IgAN and the eluate of a nephrectomized transplanted kidney from a patient with IgAN contained a 120-fold accumulation of SIgA compared with IgA1 [2,6,27].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies focused on the pathogenic role of aberrant glycosylated IgA in IgAN [7,8,9], which is deposited in mesangial areas to induce various immune inflammatory responses in IgAN, including activation of the complement path way and stimulation of mesangial cells to produce cytokines and chemokines [10,11,12,13]. However, whether patients with SIgA deposition have similar clinical pathological characteristics to patients with IgA deposition, and whether SIgA has a similar pathogenic role to IgA in IgAN are unknown.…”

Section: Introductionmentioning

confidence: 99%

Proliferation and Cytokine Production of Human Mesangial Cells Stimulated by Secretory IgA Isolated from Patients with IgA Nephropathy

Liang

Zhou

Xing

et al. 2015

Cell Physiol Biochem

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Background/Aims: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, and often aggravates by mucosal infection. Secretory IgA (SIgA) is the dominant immunoglobulin in mucosal immunity, and is deposited in the mesangium in IgAN. The biological effects of SIgA on mesangial cells are poorly understood. Methods: Deposition of SIgA in frozen renal sections from IgAN patients was detected and the association between deposition of SIgA and patients characteristics was analyzed. The biological effects of SIgA and polymeric IgA (pIgA) on human renal mesangial cells were compared. We also studied the molecular mechanism of microRNA regulating the inflammatory effects of SIgA on mesangial cells. Results: Fifty-five of 176 patients had SIgA deposition with higher incidence of infection history and hematuria, lower serum cystatin C, β2 microglobulin, blood urea nitrogen and T-grade in the Oxford classification, compared with patients without SIgA deposition. SIgA stimulated mesangial cells at a higher ratio of proliferation and higher production of interleukin (IL)-6, IL-8, monocyte chemotactic protein 1, transforming growth factor-β1 and fibronectin, compared with SIgA from healthy volunteers. The proliferation and cytokines production in mesangial cells stimulated by SIgA were significantly lower than that stimulated by pIgA. miR-16 targeted the 3′-untranslated region of IL-6 and suppressed its translation in mesangial cells induced by SIgA. Conclusions: The biological effects of SIgA on mesangial cells differ from those of pIgA. SIgA stimulates mesangial cell proliferation and production of proinflammatory cytokines. IL-6 production is regulated by miR-16 in mesangial cells.

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“…The origin of the poor galactosylated IgA1s is still a not resolved question. Several studies have documented a significant difference in IgA1s generated in the systemic compartment with respect to the IgA1s generated on the mucosal surface [48] . Mucosal IgAs are predominantly polymeric (pIgA), while systemic IgAs are monomeric.…”

Section: Salvadori M Et Al Pathophysiology Of Nephropathymentioning

confidence: 99%

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

Salvadori

Rosso

2015

WJN

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Immunoglobulin A (IgA) nephropathy is one of the most common glomerulonephritis and its frequency is probably underestimated because in most patients the disease has an indolent course and the kidney biopsy is essential for the diagnosis. In the last years its pathogenesis has been better identified even if still now several questions remain to be answered. The genetic wide association studies have allowed to identifying the relevance of genetics and several putative genes have been identified. The genetics has also allowed explaining why some ancestral groups are affected with higher frequency. To date is clear that IgA nephropathy is related to auto antibodies against immunoglobulin A1 (IgA1) with poor O-glycosylation. The role of mucosal infections is confirmed, but which are the pathogens involved and which is the role of Toll-like receptor polymorphism is less clear. Similarly to date whether the disease is due to the circulating immunocomplexes deposition on the mesangium or whether the antigen is already present on the mesangial cell as a "lanthanic" deposition remains to be clarified. Finally also the link between the mesangial and the podocyte injury and the tubulointerstitial scarring, as well as the mechanisms involved need to be better clarified.

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O-Glycosylation of Serum IgA1 Antibodies against Mucosal and Systemic Antigens in IgA Nephropathy

Cited by 112 publications

References 30 publications

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Proliferation and Cytokine Production of Human Mesangial Cells Stimulated by Secretory IgA Isolated from Patients with IgA Nephropathy

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

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