Immunoglobulin A Glycosylation and Its Role in Disease

Hansen, Alyssa L.; Reily, Colin; Novák, Jan; Renfrow, Matthew B.

doi:10.1007/978-3-030-76912-3_14

Cited by 13 publications

(9 citation statements)

References 244 publications

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“…However, the effect of Tf glycation on HK-2 cells has not been reported. Abnormal glycation of human immunoglobulin A (IgA) is associated with autoimmune disease pathogenesis, such as IgA nephropathy and IgA nephritic vasculitis ( 40 ). The apoptosis of human mesangial cells (HMCs) and HK-2 cells was accelerated, MDA levels were increased, SOD and GSH were decreased, and mRNA expression levels of RAGE and NF-κB genes were upregulated after AGE-BSA treatment in vitro ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro

Zhou

Zhao

et al. 2023

Front. Endocrinol.

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Background and objectiveGlycation is a common post-transcriptional modification of proteins. Previous studies have shown that advanced glycation end modified transferrin (AGE-Tf) levels in diabetic rat kidney tissues were increased; however, its role in diabetic nephropathy remains unclear. In this study, differences in glycation degree and Tf sites induced by differing high glucose concentrations in vitro and the effect on total iron binding capacity (TIBC) were observed. Moreover, the effect of AGE-Tf on human renal tubular epithelial cells (HK-2) was investigated.MethodsIn vitro Tf was incubated with increasing glucose concentrations (0 mM, 5.6 mM, 11.1 mM, 33.3 mM, 100 mM, 500 mM, and 1,000 mM) for AGE-Tf. Differences in AGE-Tf glycation degree and TIBC level were analyzed via colorimetric method. The AGE-Tf glycation sites were identified with LC-MS/MS. HK-2 cells were treated with AGE-Tf prepared with different glucose concentrations (33.3 mM and 500 mM) in vitro. The effects of AGE-Tf on HK-2 cell viability, proliferation, oxidative stress index, and Tf receptor expression levels were then observed.ResultsWith increasing glucose concentrations (100 mM, 500 mM, and 1,000 mM) in vitro, Tf glycation degree was significantly increased. The TIBC levels of AGE-Tf were decreased significantly with increasing glucose concentrations (33.3 mM, 100 mM, 500 mM, and 1,000 mM). Four glycated modification sites in Tf and 17 glycated modification sites were detected in AGE-Tf (500 mM) by LC-MS/MS. The structural types of AGEs were CML, G-H1, FL-1H2O, FL, and MG-H1. No significant differences were found in the survival rate of HK-2 cells among the AGE-Tf (500 mM), AGE-Tf (33.3 mM), and Tf groups (all p > 0.05). The apoptosis rate of HK-2 cells in the AGE-Tf (500 mM) group was significantly higher than that in the AGE-Tf (33.3 mM) group. Additionally, both of them were significantly higher than that in the Tf group (both p < 0.05). The MDA levels of HK-2 cells in the AGE-Tf (500 mM) and AGE-Tf (33.3 mM) groups were higher than that in the Tf group, but not significantly (both p > 0.05). The T-AOC level of HK-2 in the AGE-Tf (500 mM) group was significantly lower than that in the AGE-Tf (33.3 mM) and Tf groups (both p < 0.001). The GSH level of HK-2 cells in the AGE-Tf (500 mM) group was significantly lower than that in the Tf group (p < 0.05). The expression level of TfR in the AGE-Tf (500 mM) group was also significantly lower than that in the Tf group (p < 0.05).ConclusionThe degree and sites of Tf glycation were increased in vitro secondary to high-glucose exposure; however, the binding ability of Tf to iron decreased gradually. After HK-2 was stimulated by AGE-Tf in vitro, the apoptosis of cells was increased, antioxidant capacity was decreased, and TfR expression levels were downregulated.

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Section: Discussionmentioning

confidence: 99%

Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro

Zhou

Zhao

et al. 2023

Front. Endocrinol.

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“…distinction between aggregates) ( 101 ). One of the biggest issues are the number of glycosylation sites, because the IgA hinge region is heavily glycosylated, it is problematic to generate consistent glycoforms, as well as to implement proper quality control ( 101 , 112 , 120 , 224 ). Furthermore, the complexity of IgA in regard to protein size and glycosylation leads to lower expression yields compared to recombinant IgG ( 101 , 223 ).…”

Section: Iga As Therapeutic Antibodymentioning

confidence: 99%

A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases

Bohländer

2023

Front. Immunol.

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Inflammatory lung diseases represent a persistent burden for patients and the global healthcare system. The combination of high morbidity, (partially) high mortality and limited innovations in the last decades, have resulted in a great demand for new therapeutics. Are therapeutic IgA antibodies possibly a new hope in the treatment of inflammatory lung diseases? Current research increasingly unravels the elementary functions of IgA as protector against infections and as modulator of overwhelming inflammation. With a focus on IgA, this review describes the pathological alterations in mucosal immunity and how they contribute to chronic inflammation in the most common inflammatory lung diseases. The current knowledge of IgA functions in the circulation, and particularly in the respiratory mucosa, are summarized. The interplay between neutrophils and IgA seems to be key in control of inflammation. In addition, the hurdles and benefits of therapeutic IgA antibodies, as well as the currently known clinically used IgA preparations are described. The data highlighted here, together with upcoming research strategies aiming at circumventing the current pitfalls in IgA research may pave the way for this promising antibody class in the application of inflammatory lung diseases.

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“…Among them, the most abundant is the core 1 mono-sialylated T antigen (Neu5Acα2-3Galβ1-3GalNAc) (Takahashi et al, 2012). The truncated O-glycans, Tn (GalNAc-α1-Ser/Thr) and/or sialylated Tn (STn) were also found to distribute in a (Novak et al, 2000;Novak et al, 2018;Hansen et al, 2021).…”

Section: O-glycosylations On the Hinge Region Of Immunoglobulin Amentioning

confidence: 99%

“…(B) The core structures of O-glycans on human IgA1 are composed of GalNAc or GalNAcβ-1,3-Gal. Both of them can be modificated by Sia in different linkages ( : GalNAc; : Gal; : Sia) ( Novak et al, 2000 ; Novak et al, 2018 ; Hansen et al, 2021 ).…”

Section: Structure Of Immunoglobulin a Glycosylationmentioning

confidence: 99%

“…In addition to the above diseases, the alterations of IgA1 glycosylation are often accompanied by the development of Crohn’s disease and other autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren’s syndrome, celiac disease ( Hansen et al, 2021 ). Although the pathogenesis of them remains unknown, it has been proposed that the presence of IgA autoantibodies, aberrant IgA glycosylation, or excessive IgA immune complexes can contribute to chronic inflammation and tissue damage through the effections of FcαRI-mediated immune responses ( van Gool and van Egmond, 2020 ).…”

Section: Abnormal Of Immunoglobulin a Glycosylation With Disease Deve...mentioning

confidence: 99%

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Advances in IgA glycosylation and its correlation with diseases

et al. 2022

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Immunoglobulin A (IgA) is the most abundant immunoglobulin synthesized in the human body. It has the highest concentration in the mucosa and is second only to IgG in serum. IgA plays an important role in mucosal immunity, and is the predominant antibody used to protect the mucosal surface from pathogens invasion and to maintain the homeostasis of intestinal flora. Moreover, The binding IgA to the FcαRI (Fc alpha Receptor I) in soluble or aggregated form can mediate anti- or pro- inflammatory responses, respectively. IgA is also known as one of the most heavily glycosylated antibodies among human immunoglobulins. The glycosylation of IgA has been shown to have a significant effect on its immune function. Variation in the glycoform of IgA is often the main characteration of autoimmune diseases such as IgA nephropathy (IgAN), IgA vasculitis (IgAV), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). However, compared with the confirmed glycosylation function of IgG, the pathogenic mechanism of IgA glycosylation involved in related diseases is still unclear. This paper mainly summarizes the recent reports on IgA’s glycan structure, its function, its relationship with the occurrence and development of diseases, and the potential application of glycoengineered IgA in clinical antibody therapeutics, in order to provide a potential reference for future research in this field.

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Immunoglobulin A Glycosylation and Its Role in Disease

Cited by 13 publications

References 244 publications

Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro

Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro

A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases

Advances in IgA glycosylation and its correlation with diseases

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