Enzymatic Sialylation of IgA1 O-Glycans: Implications for Studies of IgA Nephropathy

Takahashi, Kazuo; Raška, Milan; Horynová, Milada; Hall, Stacy; Poulsen, Knud; Kilian, Mogens; Hiki, Yoshiyuki; Moldoveanu, Zina; Julian, Bruce A.; Renfrow, Matthew B.; Novák, Jan

doi:10.1371/journal.pone.0099026

Cited by 25 publications

(20 citation statements)

References 80 publications

(90 reference statements)

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“…As Type I collagen is found in abundance in bone, tendons and the dermis (20), a likely explanation for this is that CO1A1 expression spikes early in life as a result of growth, and is then downregulated in adulthood to a mainte- nance function. In contrast, Ig alpha-1 chain C region (IGHA1), a protein that plays a role in the formation of IgA antibodies (21), was shown in our analysis to exhibit higher expression as the proteome aged, with largest expressional changes observed in the neonatal to 1-5 age groups. This suggests that rapid development of the immune system occurs in the neonatal to early childhood period, and continues to mature in adolescent years and adulthood.…”

Section: Discussionmentioning

confidence: 56%

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Bjelosevic

Pascovici

Peng

et al. 2017

Molecular & Cellular Proteomics

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Human blood plasma is a complex biological fluid containing soluble proteins, sugars, hormones, electrolytes, and dissolved gasses. As plasma interacts with a wide array of bodily systems, changes in protein expression, or the presence or absence of specific proteins are regularly used in the clinic as a molecular biomarker tool. A large body of literature exists detailing proteomic changes in pathologic contexts, however little research has been conducted on the quantitation of the plasma proteome in age-specific, healthy subjects, especially in pediatrics. In this study, we utilized SWATH-MS to identify and quantify proteins in the blood plasma of healthy neonates, infants under 1 year of age, children between 1-5 years, and adults. We identified more than 100 proteins that showed significant differential expression levels across these age groups, and we analyzed variation in protein expression across the age spectrum. The plasma proteomic profiles of neonates were strikingly dissimilar to the older children and adults. By extracting the SWATH data against a large human spectral library we increased protein identification more than 6-fold (940 proteins) and confirmed the concentrations of several of these using ELISA. The results of this study map the variation in expression of proteins and pathways often implicated in disease, and so have significant clinical implication.

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Section: Discussionmentioning

confidence: 56%

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Bjelosevic

Pascovici

Peng

et al. 2017

Molecular & Cellular Proteomics

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“…Production of Gd-IgA1 in patients with IgAN has been linked to aberrant expression and activities of specific glycosylation enzymes in the Golgi apparatus for normal O -glycosylation ( 146 , 147 ). Galactose deficiency of IgA1 O -glycans can be due to a reduced rate of galactosylation or premature sialylation that would prevent addition of galactose.…”

Section: Iga1 Structure Production and Metabolismmentioning

confidence: 99%

The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy

et al. 2016

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IgA nephropathy (IgAN) is the most common primary glomerulonephritis, frequently leading to end-stage renal disease, as there is no disease-specific therapy. IgAN is diagnosed from pathological assessment of a renal biopsy specimen based on predominant or codominant IgA-containing immunodeposits, usually with complement C3 co-deposits and with variable presence of IgG and/or IgM. The IgA in these renal deposits is galactose-deficient IgA1, with less than a full complement of galactose residues on the O -glycans in the hinge region of the heavy chains. Research from the past decade led to the definition of IgAN as an autoimmune disease with a multi-hit pathogenetic process with contributing genetic and environmental components. In this process, circulating galactose-deficient IgA1 (autoantigen) is bound by antiglycan IgG or IgA (autoantibodies) to form immune complexes. Some of these circulating complexes deposit in glomeruli, and thereby activate mesangial cells and induce renal injury through cellular proliferation and overproduction of extracellular matrix components and cytokines/chemokines. Glycosylation pathways associated with production of the autoantigen and the unique characteristics of the corresponding autoantibodies in patients with IgAN have been uncovered. Complement likely plays a significant role in the formation and the nephritogenic activities of these complexes. Complement activation is mediated through the alternative and lectin pathways and probably occurs systemically on IgA1-containing circulating immune complexes as well as locally in glomeruli. Incidence of IgAN varies greatly by geographical location; the disease is rare in central Africa but accounts for up to 40% of native-kidney biopsies in eastern Asia. Some of this variation may be explained by genetically determined influences on the pathogenesis of the disease. Genome-wide association studies to date have identified several loci associated with IgAN. Some of these loci are associated with the increased prevalence of IgAN, whereas others, such as deletion of complement factor H-related genes 1 and 3, are protective against the disease. Understanding the molecular mechanisms and genetic and biochemical factors involved in formation and activities of pathogenic IgA1-containing immune complexes will enable the development of future disease-specific therapies as well as identification of non-invasive disease-specific biomarkers.

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“…The biological roles of sialic acids clustered in O-glycans of IgA1 are of great interest in IgAN but are currently not fully understood 17 . Serum IgA1 in healthy controls was found to exhibit more α2,3-sialylated O-glycans than α2,6-sialylated glycans which led to the assumption that distribution and the sites of sialic acid attachment are critically involved in the pathogenesis of IgAN.…”

Section: Iga Glycosylation and Implications For Iga Nephropathymentioning

confidence: 99%

Glyco-engineering for the production of recombinant IgA1 with distinct mucin-type O-glycans in plants

2016

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IgA nephropathy (IgAN) is a common autoimmune disease that is characterized by formation and deposition of IgA1-containing immune complexes frequently leading to end-stage kidney disease. The IgA1 in these immune complexes carries aberrantly glycosylated O-glycans. In circulating IgA1 these galactose-deficient mucin-type O-glycans are bound by autoantibodies and thus, contribute to immune complex formation and pathogenesis. Even though the disease is associated with the overproduction of aberrant O-glycans on IgA1, specific structure-function-studies of mucin-type O-glycans are limited. Compared to other expression hosts, plants offer the opportunity for de novo synthesis of O-glycans on recombinant glycoproteins as they are lacking the mammalian O-glycosylation pathway. Recently, we demonstrated that Nicotiana benthamiana are suitable for the generation of distinct O-glycans on recombinant IgA1. Here, we expand our engineering repertoire by in planta generation of galactose-deficient and α2,6-sialylated O-glycans which are the prevailing glycans detected on IgA1 from patients with IgAN.

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Enzymatic Sialylation of IgA1 O-Glycans: Implications for Studies of IgA Nephropathy

Cited by 25 publications

References 80 publications

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy

Glyco-engineering for the production of recombinant IgA1 with distinct mucin-type O-glycans in plants

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