Increased sialylation of oligosaccharides on IgG paraproteins--a potential new tumour marker in multiple myeloma.

Fleming, Simon; Smith, S; Knowles, Donald P.; Skillen, A. W.; Self, Colin H.

doi:10.1136/jcp.51.11.825

Cited by 28 publications

(14 citation statements)

References 31 publications

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“…In MGUS and MM, the glycosylation state of mc IgGs has rarely been studied. While Fleming et al ( 36 ) showed higher sialylation of IgGs from MM patients compared to MGUS patients, Nishiura et al ( 37 ) reported less galactosylated IgGs and, consequently, hyposialylated IgGs, in MM patients compared to MGUS patients and healthy volunteers (HVs). Similarly Mittermayr et al ( 38 ) recently described a decrease of IgG sialylation in a few MM patients in comparison to MGUS patients.…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins

et al. 2017

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Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients targets pathogens known to cause latent infection, a major cause of inflammation. Inflammation may influence the structure of both polyclonal (pc) Ig and mc Ig produced by malignant plasma cells via the sialylation of Ig Fc fragment. Here, we characterized the sialylation of purified mc and pc IgGs from 148 MGUS and MM patients, in comparison to pc IgGs from 46 healthy volunteers. The inflammatory state of patients was assessed by the quantification in serum of 40 inflammation-linked cytokines, using Luminex technology. While pc IgGs from MGUS and MM patients showed heterogeneity in sialylation level, mc IgGs from both MGUS and MM patients exhibited a very low level of sialylation. Furthermore, mc IgGs from MM patients were less sialylated than mc IgGs from MGUS patients (p < 0.01), and mc IgGs found to target an infectious pathogen showed a lower level of sialylation than mc IgGs of undetermined specificity (p = 0.048). Regarding inflammation, 14 cytokines were similarly elevated with a p value < 0.0001 in MGUS and in MM compared to healthy controls. MM differed from MGUS by higher levels of HGF, IL-11, RANTES and SDF-1-α (p < 0.05). MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-β1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (p < 0.05). In MGUS and in MM, the degree of sialylation of mc and pc IgGs and the levels of four cytokines important for the anti-microbial response were correlated, either positively (IFN-α2, IL-13) or negatively (IL-17, IL-33). Thus in MGUS as in MM, hyposialylation of mc IgGs is concomitant with increased levels of cytokines that play a major role in inflammation and anti-microbial response, which implies that infection, inflammation, and abnormal immune response contribute to the pathogenesis of MGUS and MM.

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Section: Introductionmentioning

confidence: 99%

Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins

et al. 2017

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“…Nishiura et al (52) found hypogalactosylated IgG paraproteins and reduced galactosyltransferase activity in bone marrow cells from patients with multiple myeloma. In contrast, other studies showed high levels of oversialylated IgG Abs in the serum from patients with multiple myeloma and increased sialyltransferase activity in their peripheral mononuclear cells (53)(54)(55). Therefore, the high sialylation observed in the anaphylactic IgG1 might be due to increased glycosyltransferase, specially sialyltransferase, activity mediated by distinct enzymes during its synthesis.…”

Section: Discussionmentioning

confidence: 85%

Sialic Acid Residues Are Essential for the Anaphylactic Activity of Murine IgG1 Antibodies

Silva

Casabuono

Jacysyn

et al. 2008

The Journal of Immunology

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Glycosylation of the Ab molecule is essential for maintaining the functional structure of Fc region and consequently for Ab-mediated effector functions, such as binding to cells or complement system activation. Alterations in the composition of the sugar moiety can dramatically influence Ab activity; however, it is not completely clear how differences in the N-linked oligosaccharide structure impact the biological function of Abs. We have described that murine IgG1 Abs can be separated according to their ability to elicit in vivo anaphylaxis in a fraction of anaphylactic and other of non-anaphylactic molecules. Furthermore, we showed that the N-linked oligosaccharide chain is essential for the structural conformation of the anaphylactic IgG1, the binding to FcγRIII on mast cells, and, consequently, for the ability to mediate anaphylactic reactions. In this study, we evaluated the contribution of individual sugar residues to this biological function. Differences in the glycan composition were observed when we analyzed oligosaccharide chains from anaphylactic or non-anaphylactic IgG1, mainly the presence of more sialic acid and fucose residues in anaphylactic molecules. Interestingly, the enzymatic removal of terminal sialic acid residues in anaphylactic IgG1 resulted in loss of the ability to trigger mast cell degranulation and in vivo anaphylactic reaction, similarly to the deglycosylated IgG1 Ab. In contrast, fucose removal did not affect the anaphylactic function. Therefore, we demonstrated that the ability of murine IgG1 Abs to mediate anaphylaxis is directly dependent on the amount of sialic acid residues associated to the oligosaccharide chain attached to the Fc region of these molecules.

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“…In human myeloma, Fab glycans occurred in about 25% of IgG paraproteins [9]. At the same time, increased sialylation of oligosaccharides on IgG paraproteins have been shown in myeloma relative to monoclonal gammopathy of undetermined significance (MGUS), which is a precursor state to MM [13]. However, novel sites for potential N-glycosylation in heavy chain V regions in myeloma displayed frequencies similar to those of normal cells, and in 8% of patients, only [46].…”

Section: Discussionmentioning

confidence: 94%

“…Nishiura et al [31] found hypogalactosylated IgG paraproteins and reduced GalT activity in bone marrow cells from patients with multiple myeloma, while Fleming et al [13], Frithz et al [14] and Cohen et al [3] demonstrated oversialylation of IgG paraproteins, an increase in ST activity in serum and peripheral mononuclear cells in patients with myeloma, all suggesting that the dysregulation of enzyme activities causing glycosylation abnormalities in immunoglobulins may perhaps reflect hyper-activation of B cells. Indeed, we found that the IgG BCR is in an activated state in myeloma [17] and that there is a correlation between sialylation of BCR IgG and IgG BCR activation state in this disease.…”

Section: Discussionmentioning

confidence: 97%

“…Thus, alterations in enzyme activities associated with glycosylation processes have been observed in plasma cells and peripheral mononuclear cells of myeloma patients [3,4,31]. IgG paraproteins were found to have abnormal oligosaccharide structures [12,13,31,40] which, additionally, were localized at unusual sites within the molecules [23]. Moreover, analysis of IgG paraproteins showed that each has an essentially unique glycosylation profile which is assumed to reflect the unique properties of the clones producing them [11,18].…”

Section: Introductionmentioning

confidence: 98%

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Glycosylation of IgG B cell receptor (IgG BCR) in multiple myeloma: relationship between sialylation and the signal activity of IgG BCR

et al. 2008

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Little is known about the glycosylation of the isotype switched B cell receptor (BCR) in multiple myeloma, and the way it might affect receptor function. In this work IgG BCRs isolated from the individual lysates of peripheral blood lymphocytes (PBL) of 32 patients with IgG multiple myeloma and healthy controls were investigated for the expression of sialic acid (SA), galactose (Gal) and N-acetylglucosamine (GlcNAc), the sugars known to specify the glycoforms of human serum IgG. The degree of glycosylation and signaling status of all 32 isolated myeloma IgG BCRs were correlated and compared with the glycosylation of the IgG paraproteins isolated from sera of the same patients. It was shown that BCR IgG in myeloma is more heavily sialylated when compared with normal controls, that the increased sialylation of IgG BCR is associated with higher levels of tyrosine phosphorylation (signaling activity) of the IgG BCR supramolecular complex and that BCR IgG and serum IgG paraprotein from the same patient differed in all cases in the levels of terminal sugar expression. The results suggest that the development of the malignant clone in MM from post-switch B cells expressing IgG BCR at their surfaces to plasma cells secreting IgG paraprotein may be followed by permanent glycosylation changes in the IgG molecules.

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Increased sialylation of oligosaccharides on IgG paraproteins--a potential new tumour marker in multiple myeloma.

Abstract: Conclusions-The ratio of neutral to sialylated oligosaccharides may act as a new marker of malignancy in IgG paraproteinaemia and warrants further investigation. (J Clin Pathol 1998;51:825-830)

Cited by 28 publications

References 31 publications

Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins

Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins

Sialic Acid Residues Are Essential for the Anaphylactic Activity of Murine IgG1 Antibodies

Glycosylation of IgG B cell receptor (IgG BCR) in multiple myeloma: relationship between sialylation and the signal activity of IgG BCR

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