Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Jones, Mark B.; Nasirikenari, Mehrab; Lugade, Amit A.; Thanavala, Yasmin; Lau, Joseph T.Y.

doi:10.1074/jbc.m112.345710

Cited by 58 publications

(48 citation statements)

References 28 publications

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“…2 A and B). However, compared with the untreated state, a decrease in the amount of sIgG was seen after sensitization, consistent with previous studies (2,14). Importantly, the percentage of OVA-specific IgG in both strains was also found to be equivalent (wild type = 6.8 ± 1.12%; cKO = 6.5 ± 1.06%), demonstrating the lack of B-cell defects associated with the loss of ST6Gal1.…”

Section: Resultssupporting

confidence: 90%

“…Germ-line ablation of ST6Gal1 eliminates α2,6-linked sialic acids on IgG and essentially all other glycoproteins in the body (10,11) with the exception of those in the central nervous system (12). Moreover, modification of the P1 region of the ST6Gal1 promoter generated defects in both myelopoiesis (13) and sialylation of serum glycoproteins (14). Here, we describe the creation of a B-cell-specific knockout of ST6Gal1 that was created to more fully understand the impact of IgG sialylation on autoimmunity.…”

mentioning

confidence: 99%

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B-cell–independent sialylation of IgG

Jones

Oswald

Joshi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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117

107

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IgG carrying terminal α2,6-linked sialic acids added to conserved N-glycans within the Fc domain by the sialyltransferase ST6Gal1 accounts for the anti-inflammatory effects of large-dose i.v. Ig (IVIg) in autoimmunity. Here, B-cell-specific ablation of ST6Gal1 in mice revealed that IgG sialylation can occur in the extracellular environment of the bloodstream independently of the B-cell secretory pathway. We also discovered that secreted ST6Gal1 is produced by cells lining central veins in the liver and that IgG sialylation is powered by serum-localized nucleotide sugar donor CMP-sialic acid that is at least partially derived from degranulating platelets. Thus, antibody-secreting cells do not exclusively control the sialylationdependent anti-inflammatory function of IgG. Rather, IgG sialylation can be regulated by the liver and platelets through the corresponding release of enzyme and sugar donor into the cardiovascular circulation.W hile en route to the plasma membrane as integral membrane proteins or for secretion, glycoproteins exiting the endoplasmic reticulum traverse the cis-, medial-, and trans-Golgi apparatus where the associated N-linked glycans are remodeled into their final form. This classically defined secretory pathway dictates that the glycoform of all glycoproteins produced by a cell is largely determined by the cohort of enzymes within the Golgi and the metabolic circumstances of that specific cell.Protein glycosylation is known to play fundamental roles in all aspects of biology, but has recently gained significant attention in immunology. When administered at high doses, i.v. Ig (IVIg) is an effective anti-inflammatory treatment for autoimmune patients (1). In 2006, it was discovered that the ∼10% of IgG molecules that carry α2,6-linked sialic acids upon the conserved biantennary N-glycans within the Fc domain provided the potent IVIg anti-inflammatory activity in autoimmune disease (2). Indeed, enrichment for the sialylated IgG (sIgG) fraction from IVIg pools increased the efficacy of treatment in mouse models of arthritis 100-fold in an IL-4-dependent fashion through receptors such as CD209 (DC-SIGN) (3, 4). Moreover, it was reported that sialylation of IgG also impacts antibody affinity maturation, although the mechanism underlying this phenomenon remains to be fully elucidated (5). These data indicate that sialylation serves as the mechanism underlying pleotropic IgG function (3,4,6).Epidemiologic analyses published since the reports cited above are consistent with this model. For example, female rheumatoid arthritis patients often go into remission during pregnancy and then relapse following childbirth. Analysis of sIgG levels before, during, and after pregnancy showed that the level of sIgG increases rapidly during pregnancy-induced remission, whereas during periods of exacerbated disease, sIgG is essentially undetectable (7,8). To date, it is unclear whether IgG sialylation patterns precede or result from the inflammatory state, and essentially nothing is known about the regulatory mecha...

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Section: Resultssupporting

confidence: 90%

mentioning

confidence: 99%

B-cell–independent sialylation of IgG

Jones

Oswald

Joshi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

117

107

View full text Add to dashboard Cite

show abstract

“…Using a mouse model, it has been reported that ST6Gal-1 deletion results in more severe pulmonary inflammation [99], consistent with the importance of sialic acid in anti-inflammation [54,56]. Recently, ST6Gal-1 driven by liver-specific promoter P1 in the systemic circulation was shown to be important for the addition of α2,6-sialic acid on the serum IgG Fc glycan [100]. As the P1 promoter does not induce the expression of ST6Gal-1 in B cells, the reduction in serum sialylated IgG in P1-deficient mice is attributed to the decreases in circulatory ST6Gal-1 [100].…”

Section: Igg Glycovariants Under Physiological and Patho-physiologicamentioning

confidence: 58%

“…Recently, ST6Gal-1 driven by liver-specific promoter P1 in the systemic circulation was shown to be important for the addition of α2,6-sialic acid on the serum IgG Fc glycan [100]. As the P1 promoter does not induce the expression of ST6Gal-1 in B cells, the reduction in serum sialylated IgG in P1-deficient mice is attributed to the decreases in circulatory ST6Gal-1 [100].…”

Section: Igg Glycovariants Under Physiological and Patho-physiologicamentioning

confidence: 99%

Antibody Glycosylation and Inflammation

2013

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IgG antibodies are the basis of some of the most effective therapeutics developed over the last 20 years. These antibodies are highly specific, have long serum-half lives, and can be produced relatively routinely, making them ideal drugs for immunotherapy. The degree of regulation on IgG antibody effector functions by the composition of the single, N-linked glycan attached to the Fc is increasingly appreciated. IgG antibodies with identical protein sequences can gain a 50-fold potency, in terms of initiating antibody-dependent cellular cytotoxicity (ADCC) by removal of the single fucose residue from the Fc glycan. Conversely, the addition of sialic acid to the terminus of the Fc glycan converts IgG antibodies into anti-inflammatory mediators, capable of suppressing autoantibody driven inflammation. This review will discuss the contribution of the Fc glycan to IgG antibody effector functions, the regulation of the antibody glycosylation in vivo, implications for the rational design of IgG antibody-based therapeutics, and touch upon the contribution of glycosylation to other immunoglobulin isotypes

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“…There is growing evidence that the IgG1 Fc N-glycan composition changes in response to disease. [44][45][46][47][48] Our data indicate variations in Fc N-glycan composition profiles alter relative FcgR binding affinities. Considering the tissue-specific expression profile for the FcgRs, 3 changes to the IgG1 Fc N-glycan composition therefore have the potential to direct which leukocyte populations are affected and, as a result, direct the body's response to infection.…”

Section: Discussionmentioning

confidence: 69%

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

Subedi

Barb

2016

mAbs

154

169

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Immunoglobulin G1 (IgG1) is the most abundant circulating human antibody and also the scaffold for many therapeutic monoclonal antibodies (mAbs). The destruction of IgG-coated targets by cell-mediated pathways begins with an interaction between the IgG Fc region and multiple varieties of membranebound Fc g receptors (FcgRs) on the surface of leukocytes. This interaction requires the presence of an asparagine-linked (N-)glycan on the Fc, and variations in the N-glycan composition can affect the affinity of CD16A binding (an FcgR). Contemporary efforts to glycoengineer mAbs focus on increasing CD16A affinity, and thus treatment efficacy, but it is unclear how these changes affect affinity for the other FcgRs. Here, we measure binding of the extracellular Fc-binding domains for human CD16A and B, CD32A, B and C, and CD64 to 6 well-defined IgG1 Fc glycoforms that cover »85% of the pool of human IgG1 Fc glycoforms. Core a1-6 fucosylation showed the greatest changes with CD16B (8.5-fold decrease), CD16A (3.9-fold decrease) and CD32B/C (1.8-fold decrease), but did not affect binding to CD32A. Adding galactose to the non-reducing termini of the complex-type, biantennary glycan increased affinity for all CD16s and 32s tested by 1.7-fold. Sialylation did not change the affinity of core-fucosylated Fc, but increased the affinity of afucosylated Fc slightly by an average of 1.16-fold for all CD16s and CD32s tested. The effects of fucose and galactose modification are additive, suggesting the contributions of these residues to Fc g receptor affinity are independent.

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Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Cited by 58 publications

References 28 publications

B-cell–independent sialylation of IgG

B-cell–independent sialylation of IgG

Antibody Glycosylation and Inflammation

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

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