Expression of IgA class switching gene in tonsillar mononuclear cells in patients with IgA nephropathy

Liu, Hong; Peng, Youming; Liu, Fuyou; Xiao, Weiwei; Li, Weiwei

doi:10.1007/s00011-011-0347-0

Cited by 19 publications

(13 citation statements)

References 51 publications

(56 reference statements)

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“…The polarization at the lymphocyte level may lead to the immune abnormalities observed in IgAN. In vitro studies have shown that tonsillar lymphocytes from IgAN patients proliferate and produce IgA in response to Haemophilus parainﬂuenzae , HS, which are isolated more frequently in tonsils from IgAN patients and deposits in the glomerular mesangium of IgAN patients [27,34]. …”

Section: Discussionmentioning

confidence: 99%

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Activation of the Interleukin-4/Signal Transducer and Activator of Transcription 6 Signaling Pathway and Homeodomain-Interacting Protein Kinase 2 Production by Tonsillar Mononuclear Cells in IgA Nephropathy

Peng²,

Liu³

et al. 2013

Am J Nephrol

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Background/Aim: Clinical development and exacerbation of IgA nephropathy (IgAN) are frequently preceded by episodes of upper respiratory tract infection such as tonsillitis. This study aimed to determine the role of the interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (STAT6) signaling pathway and homeodomain-interacting protein kinase 2 (HIPK2) in aberrant IgA1 O-glycosylation production, and identify potential therapeutic targets in IgAN. Methods: Expression levels of IL-4, STAT6, core1β1,3-galactosyltransferase (C1GALT1C1), core1β3GalT-specific molecular chaperone (Cosmc) and HIPK2 in tonsil components were examined by immunohistochemical and immunofluorescence staining. Lymphocytes isolated from 22 patients with IgAN and 24 patients with chronic tonsillitis (CT) as controls were cultured for 72 h with or without IL-4, lipopolysaccharide (LPS) and α-hemolytic streptococcus (HS) stimulation. Expression levels of STAT6, C1GALT1C1, Cosmc, HIPK2-mRNA and protein were measured by real-time PCR and Western blot analysis, respectively. The concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia villosa (VV) lectin-binding assay. To determine the contribution of HIPK2 in IgA secretion and O-glycosylation, cells were subjected to experiments for evaluation of HIPK2 silencing by Hipk2-siRNA transfection. Results: The IL-4/STAT6 signaling pathway was highly activated in all tonsil tissues (including the germinal center and tonsillar crypt epithelium) of IgAN patients, but the gene or protein expression of β1,3-Gal transferase (C1GALT1) and COSMC decreased significantly in patients with IgAN in comparison with those with CT. Hipk2 production in the tonsils derived from IgAN patients was significantly higher than that of CT patients. HIPK2-mRNA expression significantly negatively correlated with renal function as expressed by the estimated glomerular filtration rate, and also significantly positively correlated with daily proteinuria. The level of IL-4, STAT6 and HIPK2 were closely related with Lee's pathological grading system. The levels of mRNA and protein encoding STAT6 and Hipk2 in cells coincubated with IL-4, LPS and HS were significantly higher than those in the controls without stimulation; however, in the IgAN group the levels of mRNA and protein encoding C1GALT1 and Cosmc were significantly lower compared to the controls. IgA1 concentrations of supernatants in IgAN patients were remarkably higher under conditions of external stimulation. As expected, the optical density value of VV lectin binding to IgA1 increased after external stimulation in the IgAN group. By siRNA transfection, our results clearly indicate that Hipk2 negatively regulates C1GALT1 and Cosmc expression. Importantly, HIPK2-siRNA attenuates the aberrant glycosylation of IgA1 secretion. Conclusion: We identified and confirmed that activation of the IL-4/STAT6 signaling pathway has a crucial role in aberrant glycosylation of IgA1 secretion. HIPK2, a protein kinase previously unrecognized in kidney...

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Section: Discussionmentioning

confidence: 99%

“…Lysates of cultured cells were prepared as previously described [27]. Membranes were incubated with the following primary antibodies, respectively: rabbit antibody to IL-4, Hipk2, C1galT1 and COSMC (Santa Cruz Biotechnology, 1:300), and rabbit antibody to STAT6 (Epitomics, 1:500).…”

Section: Methodsmentioning

confidence: 99%

Activation of the Interleukin-4/Signal Transducer and Activator of Transcription 6 Signaling Pathway and Homeodomain-Interacting Protein Kinase 2 Production by Tonsillar Mononuclear Cells in IgA Nephropathy

Peng²,

Liu³

et al. 2013

Am J Nephrol

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“…In addition to yielding a sterile Iα-Cα mRNA, GLT renders the Cα gene substrate for AID, an essential component of the CSR machinery [6] . Our previous studies using tonsil mononuclear cells (TMCs) indicated that TMCs from patients with IgAN are capable of producing high levels of IgA and IgA1 when stimulated with lipopolysaccharide (LPS) or hemolytic streptococcus (HS), which may be due to the increased expression of AID and Iα-Cα [7] .…”

Section: Regulation Of Iga Class Switch Recombination Inmentioning

confidence: 99%

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

Peng²,

Chen³

et al. 2016

Am J Nephrol

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Background: Immunoglobulin (Ig) A nephropathy (IgAN) is the ﬁnding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Increasing evidence suggested that retinoic acid (RA) signaling selectively induces IgA isotype switching and basic leucine zipper transcription factor, ATF-like (BATF) controls the global regulators of class switch recombination (CSR) in lymphocytes. Great effort has been paid to identify whether impaired immune regulation along the ‘mucosa-bone marrow (BM) axis' play an important role in the pathogenesis of IgAN. Methods: The aim of the study was to investigate the expression of all-trans-RA (ATRA) and BATF, and to identify their impact on IgA CSR in IgAN patients and rat animal models. Blood samples and tonsillar tissue specimens were obtained from 22 patients with IgAN and 24 patients with chronic tonsillitis as control. Results: Immunohistochemical, RT-PCR and western blotting examination revealed that RA signaling and BATF productions are activated in IgAN patients compared with controls. Lipopolysaccharide and α-hemolytic streptococcus stimulation upregulated RA receptor (RAR) and BATF expression, promote IgA CSR and ATRA productions in tonsil mononuclear cells. RAR alpha (RARα) or BATF siRNA decreases IgA expression. We also built IgAN rat models and found that RARα, BATF and activation-induced cytidine deaminase were upregulated in the peripheral blood, spleen and BM. With ATRA (500 μg/kg body weight) treatment for 8 weeks, IgA deposition on glomeruli and mesangial cells proliferation increased. It also revealed that ATRA activated BATF and IgA CSR in vivo. Conclusion: These data point toward the role of RA signaling together with BATF in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with neoantigen results in impaired mucosal and systemic IgA responses.

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“…18 But in our previous study, we stimulated TMCs of patients with IgAN by hemolytic streptococcus and found that not only levels of IgA and IgA1 significantly increased but also elevated expression levels of Ia-Ca and activation-induced cytidine deaminase (AID). 15 As members of the apolipoprotein B mRNA-enzyme catalytic polypeptide (APOBEC) cytidine deaminase family of proteins, AID is expressed in B cells inducing class switch recombination of the m constant region to g, a, and , thereby changing the antibody isotype from IgM to IgG, IgA, and IgE. 7,24 In addition, with other cytokines, assistance BAFF can induce germline Ca gene expression, AID expression, and IgA class switching in a CD40-independent manner.…”

Section: Iga Csr: In Response To Baff It Induced Iga Hyper-productionmentioning

confidence: 99%

“…14 Our previous study revealed that IgA and IgA1 levels in tonsillar mononuclear cells (TMCs) stimulated with 10 mg/mL of lipopolysaccharide or 1 Â 10 8 cfu/mL of hemolytic streptococcus were markedly increased compared with the control group in patients with IgAN. 15 High expression of tonsillar TLR9 was observed in some IgAN patients, who showed stronger and earlier remission of hematuria and proteinuria than those with low TLR9 expression after tonsillectomy with steroid pulse therapy (SPT). 16 Taken together, MALT infections induce CpG-DNA in pathogenic bacterium recognized by TLR9 and up-regulate IgA production, finally result in aggravation of IgAN.…”

mentioning

confidence: 99%

New insights into the pathogenesis of IgA nephropathy: do toll like receptor 9-B cell activation factor-IgA class switching recombination signaling axis induce IgA hyper-production?

Liu

Peng

et al. 2014

Renal Failure

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Expression of IgA class switching gene in tonsillar mononuclear cells in patients with IgA nephropathy

Cited by 19 publications

References 51 publications

Activation of the Interleukin-4/Signal Transducer and Activator of Transcription 6 Signaling Pathway and Homeodomain-Interacting Protein Kinase 2 Production by Tonsillar Mononuclear Cells in IgA Nephropathy

Activation of the Interleukin-4/Signal Transducer and Activator of Transcription 6 Signaling Pathway and Homeodomain-Interacting Protein Kinase 2 Production by Tonsillar Mononuclear Cells in IgA Nephropathy

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

New insights into the pathogenesis of IgA nephropathy: do toll like receptor 9-B cell activation factor-IgA class switching recombination signaling axis induce IgA hyper-production?

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