Skip to main content

Main menu

  • Home
  • Content
    • First Release
    • Current
    • Archives
    • Collections
    • Audiovisual Rheum
    • 50th Volume Reprints
  • Resources
    • Guide for Authors
    • Submit Manuscript
    • Payment
    • Reviewers
    • Advertisers
    • Classified Ads
    • Reprints and Translations
    • Permissions
    • Meetings
    • FAQ
    • Policies
  • Subscribers
    • Subscription Information
    • Purchase Subscription
    • Your Account
    • Terms and Conditions
  • About Us
    • About Us
    • Editorial Board
    • Letter from the Editor
    • Duncan A. Gordon Award
    • Privacy/GDPR Policy
    • Accessibility
  • Contact Us
  • JRheum Supplements
  • Services

User menu

  • My Cart
  • Log In

Search

  • Advanced search
The Journal of Rheumatology
  • JRheum Supplements
  • Services
  • My Cart
  • Log In
The Journal of Rheumatology

Advanced Search

  • Home
  • Content
    • First Release
    • Current
    • Archives
    • Collections
    • Audiovisual Rheum
    • 50th Volume Reprints
  • Resources
    • Guide for Authors
    • Submit Manuscript
    • Payment
    • Reviewers
    • Advertisers
    • Classified Ads
    • Reprints and Translations
    • Permissions
    • Meetings
    • FAQ
    • Policies
  • Subscribers
    • Subscription Information
    • Purchase Subscription
    • Your Account
    • Terms and Conditions
  • About Us
    • About Us
    • Editorial Board
    • Letter from the Editor
    • Duncan A. Gordon Award
    • Privacy/GDPR Policy
    • Accessibility
  • Contact Us
  • Follow Jrheum on BlueSky
  • Follow jrheum on Twitter
  • Visit jrheum on Facebook
  • Follow jrheum on LinkedIn
  • Follow jrheum on YouTube
  • Follow jrheum on Instagram
  • Follow jrheum on RSS
Research ArticleArticle

IgG Glycosylation Changes and MBL2 Polymorphisms: Associations with Markers of Systemic Inflammation and Joint Destruction in Rheumatoid Arthritis

LONE N. TROELSEN, SØREN JACOBSEN, JODIE L. ABRAHAMS, LOUISE ROYLE, PAULINE M. RUDD, EVA NARVESTAD, NIELS H. HEEGAARD and PETER GARRED
The Journal of Rheumatology March 2012, 39 (3) 463-469; DOI: https://doi.org/10.3899/jrheum.110584
LONE N. TROELSEN
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: lone.troelsen@mail.dk
SØREN JACOBSEN
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
JODIE L. ABRAHAMS
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
LOUISE ROYLE
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
PAULINE M. RUDD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
EVA NARVESTAD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
NIELS H. HEEGAARD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
PETER GARRED
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • References
  • PDF
PreviousNext
Loading

Abstract

Objective. To examine whether IgG glycosylation changes and MBL2 genotypes are associated with systemic inflammation and joint destruction in rheumatoid arthritis (RA).

Methods. IgG N-glycan content was determined from serum in 118 patients with RA by high-throughput glycan analysis using normal-phase high-pressure liquid chromatography. MBL2 extended genotypes (YA/YA, YA/XA, XA/XA, YA/YO, XA/YO, YO/YO) were determined. Systemic inflammation was assessed by serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). Joint destruction was assessed by total Sharp score (TSS) and alloplastic surgery records.

Results. IgG hypogalactosylation was significantly correlated to IL-6 (Spearman’s rho = 0.32, p < 0.001), CRP (Spearman’s rho = 0.31, p < 0.001), TSS (Spearman’s rho = 0.25, p = 0.01), and alloplastic replacement of joints (Spearman’s rho = 0.18, p = 0.05). In multivariate analysis including age, CRP, anticitrullinated protein antibodies (ACPA), and other confounders, IgG hypogalactosylation was significantly associated with TSS (p = 0.014) and alloplastic joint replacement (OR 76.5, p = 0.041) in patients homozygous for the high expression MBL2 genotype YA/YA, but not in carriers of lower expression genotypes.

Conclusion. Decreased galactosylation of IgG correlated to markers of inflammation, i.e., IL-6 and CRP. Only in patients homozygous for high expression of the MBL2 genotype YA/YA was IgG hypogalactosylation associated with markers of joint destruction. Our results suggest that inflammation-associated decreased galactosylation of IgG combined with high expression MBL2 genotypes are involved in the pathophysiology of RA.

Key Indexing Terms:
  • RHEUMATOID ARTHRITIS
  • IMMUNOGLOBULIN G
  • GALACTOSE
  • MANNOSE-BINDING LECTIN
  • RISK FACTORS
  • PROGNOSIS

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology affecting about 1% of the adult population. RA is characterized by synovial inflammation and joint destruction leading to impaired joint function. The course of RA is variable and different markers of prognostic value have been discussed. Acute-phase reactants, especially C-reactive protein (CRP), have been shown to be highly reliable markers of disease activity and in the long term are associated with radiographic outcomes1,2 and high titers of rheumatoid factor (RF), and antibodies against citrullinated protein (ACPA) are associated with progression of radiographic signs of joint destruction3,4,5.

Human IgG is a glycoprotein with 2 conserved N-linked glycosylation sites. One of the glycans is present at Asn-297 on each heavy chain in the CH2 domain (Fc portion). The other N-glycan is attached to the hypervariable region of the Fab arm in about 20% of circulating IgG, and is heavily sialylated. The N-glycans at Asn-297 are of complex biantennary type with a heptasaccharide core that terminates in 2 N-acetylglucosamine (GlcNac) residues onto which may be added core fucose, bisecting GlcNAc, terminating galactose, and sialic acid, giving rise to the presence of multiple glycoforms (Figure 1). Based on the presence or absence of terminal galactose on Asn-297 glycans, IgG have been divided into 3 categories: nongalactosylated (G0), monogalactosylated (G1), and digalactosylated (G2) IgG. In healthy individuals the IgG G0 glycoform accounts for about 20%–35% of the total IgG glycan pool, but in patients with RA serum levels of IgG G0 may rise 3-fold6. Serum levels of hypogalactosylated IgG also increase with age7,8. Studies indicate that decreased galactosylation of IgG may be of diagnostic and prognostic value in RA9,10,11,12,13.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Structure of the complex biantennary oligosaccharide at Asn-297. Solid lines indicate core heptasaccharide; broken lines: additional sugars that may be added. Fuc: fucose; GlcNAc: N-acetylglucosamine; Gal: galactose; Man: mannose; Neu5Ac: sialic acid.

Mannose-binding lectin (MBL) is a liver-derived component of the innate immune system that may bind to various sugar motifs on microorganisms and apoptotic cells and thereby activate complement through MBL-associated serine proteases. Serum concentrations of MBL mainly reflect the expression of the MBL2 gene in the liver. Subjects homozygous or compound-heterozygous for defective structural MBL2 alleles produce dysfunctional low molecular weight MBL with little or no apparent biological function, whereas subjects with the extended YA/YA genotype have the highest MBL-producing potential14.

MBL may play differentiated roles in the pathogenesis of RA. In some studies MBL deficiency has been associated with erosive disease15,16. Other studies have been inconclusive in this regard17,18. Conversely, the high-expressing MBL2 YA/YA genotype has a synovitis-enhancing effect in ACPA-positive patients with early RA19 and high serum levels of MBL are associated with increased risk of developing RA20 and with increased overall and cardiovascular mortality in RA21.

In vitro MBL interacts with the IgG G0 glycoform through the exposed GlcNac and thereby activates complement22. In one study we observed that high serum levels of the IgG G0 glycoform in combination with genetically determined high serum levels of MBL were associated with development of ischemic heart disease in patients with RA23. Moreover, a previous study suggested that MBL/IgG G0 complexes may increase inflammation in late-onset and rapidly progressive RA24.

We used a recently developed high-throughput method for IgG glycan quantification25 in this study. We examined if IgG hypogalactosylation and MBL2 genotypes were associated with markers of systemic inflammation and joint destruction in patients with RA. We also investigated possible interaction between hypogalactosylated IgG and the high-expressing MBL2 YA/YA genotype with respect to joint damage.

MATERIALS AND METHODS

Patients

One hundred eighteen consecutive unrelated white Danish patients with RA attending the Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, were included from October 2006 to March 2007 as described26. The median disease duration at inclusion was 12 years (range 1–41 yrs). All patients fulfilled the American College of Rheumatology 1987 classification criteria for RA27. At inclusion, all patients underwent a detailed interview and a clinical examination. Posteroanterior (PA) and PA oblique radiographs of hands and feet were taken. Serum samples and whole EDTA blood for DNA extraction were collected and stored at −80°C.

Our study was approved by the local scientific ethical committee (reference no. KF 01286984). Written informed consent was obtained from each patient.

Clinical and laboratory assessment

Demographics, disease descriptors, and comorbidities recorded were as follows: (1) sex and age at inclusion; (2) numbers of tender and swollen joints; (3) presence of serum ACPA and RF; (4) current treatment with glucocorticoids, methotrexate (MTX), and tumor necrosis factor-α (anti-TNF-α) drugs; (5) history of ischemic heart disease; (6) history of diabetes; and (7) smoking status calculated as “pack-years” [number of packs (20 cigarettes) per day times number of years]. The following outcome variables were assessed: (1) systemic inflammation measured by serum levels of interleukin 6 (IL-6), CRP, and TNF-α; and (2) joint destruction, evaluated according to the principles of the Sharp/van der Heijde scoring method [total Sharp score (TSS), possible range 0–448]28 and alloplastic surgery records. All patients were interviewed and examined by the same physician, and the same radiologist evaluated all radiographs of hands and feet without knowledge of other study data. In 10 cases it was not possible to calculate TSS because of previous articular surgery and no available radiographs to which the last-observation-carry-forward method could be applied. Five of these belonged to the group of patients with alloplastic surgery (n = 27) and 5 belonged to the group without alloplastic surgery (n = 91). All the alloplastic surgeries were performed because of joint destruction caused by chronic inflammation, e.g., destruction of joint surface and deformity. Clinical charts were used to verify information regarding alloplastic surgery and treatment with antirheumatic drugs.

Quantification of IgG G0 glycoforms

IgG N-glycan analysis was performed using a 96-well plate in-gel block high-throughput glycan analysis method as described25. N-glycans were released from the serum samples by N-glycosidase F (PNGase F; Prozyme, San Leandro, CA, USA) and fluorescent labeled with 2-aminobenzamide (2AB; LudgerTag 2AB labeling kit; Ludger, Abingdon, UK) and analyzed by normal phase high-pressure liquid chromatography (NP-HPLC) with a 60-min run time. Peak retention times were expressed as glucose unit values relative to a 2AB–dextran ladder standard (glucose homopolymer) using Empower GPC software (Waters Corp., Milford, MA, USA). Structural assignments of the NP-HPLC glycan profile data were performed by database matching using Glycobase29. The content of IgG G0 glycoforms in serum was expressed as the ratio of core fucosylated nongalactosylated (FG0) to core fucosylated monogalactosylated (FG1).

MBL2 genotypes

Detection of MBL2 genotypes was as described30. All patients were genotyped for 3 MBL2 structural polymorphisms and for a promoter polymorphism in position −221 (X/X, X/Y, Y/Y). Patients were stratified into those with the extended YA/YA genotype (high-producing) and those with low and intermediate MBL-producing genotypes (non-YA/YA genotypes: YA/XA, XA/XA, YA/YO, XA/YO, and YO/YO).

Statistical analysis

Nonparametric analyses (Spearman’s rank correlation, Mann-Whitney test) were initially used to examine the relation between FG0/FG1 ratio, MBL2 genotypes, and markers of inflammation and joint destruction. Logarithmic transformation of FG0/FG1 ratio allowed the relations between FG0/FG1 ratio, CRP, IL-6, and TSS to be further determined by simple and multivariate linear regression analyses. The relations between FG0/FG1 ratio and alloplastic surgery were analyzed by univariate and multivariate logistic regression analyses. Adjustment variables in the multivariate analyses of CRP and IL-6 were sex, age, ACPA, and treatment with antirheumatic drugs; in the multivariate analysis of TSS and alloplastic surgery, CRP was included in addition to the variable mentioned above. All regression analyses were repeated among patients with the extended YA/YA genotype and patients with the non-YA/YA genotypes. Equality of regression coefficients was tested by calculating the Z score. Statistical processing was performed with SPSS 15. Statistical significance was defined as p value < 0.05.

RESULTS

Clinical and laboratory variables at inclusion for all patients, patients with the extended YA/YA genotype (n = 43; 36%), and patients with the non-YA/YA genotype (n = 75; 64%) are shown in Table 1. The mean FG0/FG1 ratio was 1.18 ± 0.41 and the median FG0/FG1 ratio was 1.12 (range 0.6–3.3). The mean FG0/FG1 ratio was 1.21 ± 0.47 among patients with the YA/YA genotype and 1.17 ± 0.38 among patients with the non-YA/YA genotype. Using Levene’s test for equality of variance we found no difference in the FG0/FG1 ratio between patients with the YA/YA genotype and those with the non-YA/YA genotype (p = 0.57). We found no significant correlations between the FG0/FG1 ratio and disease descriptors, i.e., tender and swollen joint counts, RF, ACPA, and treatment with antirheumatic drugs.

View this table:
  • View inline
  • View popup
Table 1.

Clinical and laboratory variables assessed in the cohort of 118 patients with rheumatoid arthritis (RA).

Markers of systemic inflammation

Results of Spearman’s rank correlation analyses between FG0/FG1 ratio and markers of systemic inflammation are shown in Table 2. FG0/FG1 ratio was significantly correlated to IL-6 (correlation coefficient 0.32, p < 0.001) and CRP (correlation coefficient 0.31, p = 0.001). There were no significant correlations between FG0/FG1 ratio and TNF-α (correlation coefficient −0.09, p = 0.32). Using the Mann-Whitney test we found no differences in IL-6, CRP, or TNF-α between patients with the extended YA/YA genotype and patients with the non-YA/YA genotypes.

View this table:
  • View inline
  • View popup
Table 2.

Results of Spearman rank correlation analysis between FG0/FG1 ratio and outcome variables.

Table 3 shows that the FG0/FG1 ratio was significantly associated with IL-6 and CRP in both simple and multivariate linear regression analyses including all patients. However, these associations did not differ between patients with the extended YA/YA genotype and patients with the non-YA/YA genotypes.

View this table:
  • View inline
  • View popup
Table 3.

Results of linear regression analyses examining the association between FG0/FG1 ratio* and C-reactive protein (CRP), interleukin 6 (IL-6), and total Sharp score (TSS).

Joint destruction

Using Spearman’s correlation analysis we found that the FG0/FG1 ratio was significantly correlated to TSS (correlation coefficient 0.25, p = 0.01) and to alloplastic replacement of joints (correlation coefficient 0.18, p = 0.05; Table 2). Using the Mann-Whitney test we found no significant difference in TSS or alloplastic replacement of joints between patients with the extended YA/YA genotype and patients with the non-YA/YA genotypes.

Simple regression analysis showed a significant linear association between FG0/FG1 ratio and TSS for all patients (regression coefficient 110, p = 0.041). However, upon dividing the patients into 2 groups based on the MBL2 genotypes we found that this linear association was significant in patients with the extended YA/YA genotype (regression coefficient 243, p = 0.003) and not in patients with the non-YA/YA genotypes (regression coefficient 20.7, p = 0.772; Table 3). In multivariate linear regression analysis allowing adjustment for confounders we found that the linear association between FG0/FG1 ratio and TSS remained significant in patients with the extended YA/YA genotype (regression coefficient 272, p = 0.014; Table 3).

Table 4 shows that the FG0/FG1 ratio was significantly associated with alloplastic replacement of joints in univariate logistic regression analysis including all patients and patients with the extended YA/YA genotype (OR 3.27, p = 0.022; OR 13.9, p = 0.017) but not in patients with the non-YA/YA genotypes (OR 1.49, p = 0.57). In the multivariate analysis FG0/FG1 ratio only remained significantly associated with alloplastic replacement of joints in patients with the extended YA/YA genotype (OR 76.5, p = 0.041).

View this table:
  • View inline
  • View popup
Table 4.

Results of logistic regression analysis examining the association between FG0/FG1 ratio and alloplastic surgery.

Further, we found that the FG0/FG1 ratio association with TSS and alloplastic replacement of joints differed significantly between patients with the extended YA/YA genotype and patients with the non-YA/YA genotypes, being highest in the first group (Tables 3 and 4).

DISCUSSION

In our study of 118 patients with RA we used a validated high-throughput method for IgG glycan quantification9. Our results showed that the FG0/FG1 ratio was associated with IL-6 and CRP. Moreover, in patients homozygous for the high-expression MBL2 YA/YA genotype, the FG0/FG1 ratio was significantly associated with markers of joint destruction independent of age, CRP, ACPA status, and other potential confounders.

In a recent study by Ercan, et al9 the mean FG0/FG1 ratio was 1.36 ± 0.43. In our study the mean FG0/FG1 ratio was 1.18 ± 0.41, which is relatively low given the age of the patients in our cohort. However, the low FG0/FG1 ratio in our study could be explained by the fact that our RA population generally had low disease activity, with a mean Disease Activity Score 28-CRP (DAS28-CRP) of 3.09 ± 1.35 (mean DAS28-CRP in the study by Ercan, et al9 was 4.15 ± 1.74) due to effective medication of most patients with MTX and/or TNF-α inhibitors at the time of inclusion. The low disease activity could also explain the lack of significant relations between hypogalactosylated IgG and number of tender and swollen joints in our study compared to the study by Ercan, et al9. Despite these differences both studies showed highly significant associations between the FG0/FG1 ratio and markers of systemic inflammation, suggesting that IgG hypogalactosylation may reflect the inflammatory process in RA. As the overall regulation of IgG glycosylation in plasma cells is not fully understood, future investigations may include studies on how various cytokines and immune factors influence the glycosyltransferases activities that determine the composition of the arms of the N-glycans.

We found that the FG0/FG1 ratio was significantly associated with radiographic scores of joint destruction and alloplastic joint replacement in patients homozygous for the high-expression MBL2 YA/YA genotype but not in carriers of lower-expression genotypes. These results were consistent in both univariate and multivariate analysis with adjustment for sex, age, CRP, ACPA status, and immunomodulatory treatment. Further, the differences observed in the associations were statistically significant, lending validity to the concept that the coexistence of hypogalactosylated IgG and MBL may have a negative influence on joint integrity in RA.

In a previous study24, a weak correlation was observed between erosion score and hypogalactosylated IgG in patients with RA who are homozygous for the normal MBL2 genotype. Moreover, we have recently shown that high serum levels of MBL in combination with high serum levels of IgG G0 glycoforms confer a significant risk of developing ischemic heart disease including acute myocardial infarction in patients with RA23. Our observation that hypogalactosylated IgG associates only with markers of joint damage in patients with the high-expressing MBL2 YA/YA genotype parallels these previous findings, and is in accord with the hypothesis that MBL and IgG G0 complexes are harmful in RA22. However, it remains to be proven experimentally that complexes of IgG G0 and MBL participate in the development of destructive joint pathology in RA. Thus we cannot exclude that our observation reflects coexisting, but independent pathophysiological change events indirectly associated with the clinical events studied.

Glycosylation changes could also be linked to inflammation and to the pathogenesis of RA in other ways. A previous study showed that absence of sialic acid on IgG results in proinflammatory responses through engagement of specific Fc receptors on effector cells31,32. As IgG-Fc degalactosylation inevitably leads to decreased amounts of sialic acid attached to IgG-Fc it could be suggested that desialylation also plays an important role in the inflammatory processes in RA.

Fucose on IgG heavy chains is increased in patients with RA compared to healthy controls33 and increased IgG fucosylation was found to be a diagnostic marker in juvenile chronic arthritis34. As fucose may alter antibody-dependent cellular cytotoxicity by affecting the binding of IgG to FcγRIIIa35, fucosylation changes on IgG heavy chains may also play a role in the pathogenesis of RA. In this respect the FG0/FG1 ratio, which is based on fucosylated G0 and fucosylated G1, may be a more relevant measurement compared to the classical %G0, which includes fucosylated as well as nonfucosylated G0, G1, and G2 Fc-glycans.

We did not find a significant difference between the high-expressing MBL2 YA/YA genotype and the non-YA/YA genotypes with respect to markers of disease activity or joint destruction, which is in line with findings in 2 studies17,18. However, the results concerning the role of MBL in RA are divergent and it is likely that differences in study design, differences in medication, age and duration of disease, and confounders such as IgG G0 may have influenced the observed associations. Several pathophysiological mechanisms have been discussed in relation to the role of MBL in RA. It has been hypothesized that MBL deficiency may result in defective clearance of pathogens and circulating immune complexes as well as dying host cells and cellular debris, thereby aggravating ongoing joint inflammation leading to joint damage in RA. In contrast, the high-expressing MBL2 genotypes could be associated with excess joint inflammation and increased joint destruction.

We show that decreased IgG galactosylation is associated with systemic inflammation in RA and that the presence of decreased IgG galactosylation and high-expression MBL2 genotypes may contribute to the pathogenesis of RA. These findings need to be corroborated by experimental studies examining the molecular details of the putative MBL/IgG G0 interaction in vivo. As IgG hypogalactosylation is also increased in other inflammatory diseases36,37,38, future studies may address whether our findings are applicable beyond RA.

Acknowledgment

Matthew Campbell from Dublin-Oxford Glycobiology Laboratory is acknowledged for his critical reading of the manuscript.

Footnotes

  • Supported by grants from the Danish Rheumatism Association, The Novo Nordisk Research Foundation, The Capital Region of Denmark, and Rigshospitalet, Copenhagen University Hospital.

  • Accepted for publication November 18, 2011.

REFERENCES

  1. 1.↵
    1. Aletaha D,
    2. Nell VP,
    3. Stamm T,
    4. Uffmann M,
    5. Pflugbeil S,
    6. Machold K,
    7. et al.
    Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: Validation of a clinical activity score. Arthritis Res Ther 2005;7:796–806.
    OpenUrlCrossRef
  2. 2.↵
    1. Van Leeuwen MA,
    2. Van Rijswijk MH,
    3. Sluiter WJ,
    4. van Riel PL,
    5. Kuper IH,
    6. van de Putte LB,
    7. et al.
    Individual relationship between progression of radiological damage and the acute phase response in early rheumatoid arthritis. Towards development of a decision support system. J Rheumatol 1997;24:20–7.
    OpenUrlPubMed
  3. 3.↵
    1. Bukhari M,
    2. Lunt M,
    3. Harrison BJ,
    4. Scott DG,
    5. Symmons DP,
    6. Silman AJ
    . Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: Results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum 2002;46:906–12.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Quinn MA,
    2. Gough AK,
    3. Green MJ,
    4. Devlin J,
    5. Hensor EM,
    6. Greenstein A,
    7. et al.
    Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology 2006;45:478–80.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. van Gaalen FA,
    2. van Aken J,
    3. Huizinga TW,
    4. Schreuder GM,
    5. van Breedveld FC,
    6. Zanelli E,
    7. et al.
    Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum 2004;50:2113–21.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Parekh RB,
    2. Dwek RA,
    3. Sutton BJ,
    4. Fernandes DL,
    5. Leung A,
    6. Stanworth D,
    7. et al.
    Association of rheumatoid arthritis and primary osteo-arthritis with changes in the glycosylation pattern of total serum IgG. Nature 1985;316:452–7.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Parekh R,
    2. Roitt I,
    3. Isenberg D,
    4. Dwek R,
    5. Rademacher T
    . Age-related galactosylation of the N-linked oligosaccharides of human serum IgG. J Exp Med 1988;167:1731–6.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Yamada E,
    2. Tsukamoto Y,
    3. Sasaki R,
    4. Yagyu K,
    5. Takahashi N
    . Structural changes of immunoglobulin G oligosaccharides with age in healthy human serum. Glycoconj J 1997;14:401–5.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Ercan A,
    2. Cui J,
    3. Chatterton DE,
    4. Deane KD,
    5. Hazen MM,
    6. Brintnell W,
    7. et al.
    IgG galactosylation aberrancy precedes disease onset, correlates with disease activity and is prevalent in autoantibodies in rheumatoid arthritis. Arthritis Rheum 2010;62:2239–48.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Gindzienska-Sieskiewicz E,
    2. Klimiuk PA,
    3. Kisiel DG,
    4. Gindzienski A,
    5. Sierakowski S
    . The changes in monosaccharide composition of immunoglobulin G in the course of rheumatoid arthritis. Clin Rheumatol 2007;26:685–90.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Lacki JK,
    2. Porawska W,
    3. Mackiewicz U,
    4. Mackiewicz S,
    5. Muller W
    . Changes in agalactosyl IgG levels correlate with radiological progression in early rheumatoid arthritis. Ann Med 1996;28:265–9.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Pasek M,
    2. Duk M,
    3. Podbielska M,
    4. Sokolik R,
    5. Szechinski J,
    6. Lisowska E,
    7. et al.
    Galactosylation of IgG from rheumatoid arthritis (RA) patients — Changes during therapy. Glycoconj J 2006;23:463–71.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Vanzeben D,
    2. Rook GAW,
    3. Hazes JMW,
    4. Zwinderman AH,
    5. Zhang Y,
    6. Ghelani S,
    7. et al.
    Early agalactosylation of IgG is associated with a more progressive disease course in patients with rheumatoid arthritis — Results of a follow-up study. Br J Rheumatol 1994;33:36–43.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Garred P,
    2. Larsen F,
    3. Madsen HO,
    4. Koch C
    . Mannose-binding lectin deficiency — revisited. Mol Immunol 2003;40:73–84.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Graudal NA,
    2. Madsen HO,
    3. Tarp U,
    4. Svejgaard A,
    5. Jurik AG,
    6. Graudal HK,
    7. et al.
    The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 2000;43:515–21.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Jacobsen S,
    2. Madsen HO,
    3. Klarlund M,
    4. Jensen T,
    5. Skjodt H,
    6. Jensen KE,
    7. et al.
    The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. J Rheumatol 2001;28:935–42.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Barton A,
    2. Platt H,
    3. Salway F,
    4. Symmons D,
    5. Lunt M,
    6. Worthington J,
    7. et al.
    Polymorphisms in the mannose binding lectin (MBL) gene are not associated with radiographic erosions in rheumatoid or inflammatory polyarthritis. J Rheumatol 2004;31:442–7.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Van de Geijn FE,
    2. Hazes JM,
    3. Geleijns K,
    4. Emonts M,
    5. Jacobs BC,
    6. Dufour-van den Goorbergh BC,
    7. et al.
    Mannose-binding lectin polymorphisms are not associated with rheumatoid arthritis — Confirmation in two large cohorts. Rheumatology 2008;47:1168–71.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Jacobsen S,
    2. Garred P,
    3. Madsen HO,
    4. Heegaard NH,
    5. Hetland ML,
    6. Stengaard-Pedersen K,
    7. et al.
    Mannose-binding lectin gene polymorphisms are associated with disease activity and physical disability in untreated, anti-cyclic citrullinated peptide-positive patients with early rheumatoid arthritis. J Rheumatol 2009;36:731–5.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Saevarsdottir S,
    2. Steinsson K,
    3. Grondal G,
    4. Valdimarsson H
    . Patients with rheumatoid arthritis have higher levels of mannan-binding lectin than their first-degree relatives and unrelated controls. J Rheumatol 2007;34:1692–5.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Troelsen LN,
    2. Garred P,
    3. Jacobsen S
    . Mortality and predictors of mortality in rheumatoid arthritis — A role for mannose-binding lectin? J Rheumatol 2010;37:536–43.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Malhotra R,
    2. Wormald MR,
    3. Rudd PM,
    4. Fischer PB,
    5. Dwek RA,
    6. Sim RB
    . Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nat Med 1995;1:237–43.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Troelsen LN,
    2. Garred P,
    3. Madsen HO,
    4. Jacobsen S
    . Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis. Arthritis Rheum 2007;56:21–9.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Garred P,
    2. Madsen HO,
    3. Marquart H,
    4. Hansen TM,
    5. Sorensen SF,
    6. Petersen J,
    7. et al.
    Two edged role of mannose binding lectin in rheumatoid arthritis: A cross sectional study. J Rheumatol 2000;27:26–34.
    OpenUrlPubMed
  25. 25.↵
    1. Royle L,
    2. Campbell MP,
    3. Radcliffe CM,
    4. White DM,
    5. Harvey DJ,
    6. Abrahams JL,
    7. et al.
    HPLC-based analysis of serum N-glycans on a 96-well plate platform with dedicated database software. Anal Biochem 2008;376:1–12.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Troelsen LN,
    2. Garred P,
    3. Christiansen B,
    4. Torp-Pedersen C,
    5. Christensen IJ,
    6. Narvestad E,
    7. et al.
    Double role of mannose-binding lectin in relation to carotid intima-media thickness in patients with rheumatoid arthritis. Mol Immunol 2010;47:713–8.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Arnett FC,
    2. Edworthy SM,
    3. Bloch DA,
    4. McShane DJ,
    5. Fries JF,
    6. Cooper NS,
    7. et al.
    The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. van der Heijde DM
    . How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 2000;27:261–3.
    OpenUrlPubMed
  29. 29.↵
    1. Campbell MP,
    2. Royle L,
    3. Radcliffe CM,
    4. Dwek RA,
    5. Rudd PM
    . GlycoBase and autoGU: Tools for HPLC-based glycan analysis. Bioinformatics 2008;24:1214–6.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    1. Madsen HO,
    2. Garred P,
    3. Thiel S,
    4. Kurtzhals JAL,
    5. Lamm LU,
    6. Ryder LP,
    7. et al.
    Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 1995;155:3013–20.
    OpenUrlAbstract
  31. 31.↵
    1. Burton DR,
    2. Dwek RA
    . Immunology. Sugar determines antibody activity. Science 2006;313:627–8.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Kaneko Y,
    2. Nimmerjahn F,
    3. Ravetch JV
    . Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006;313:670–3.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Gornik I,
    2. Maravic G,
    3. Dumic J,
    4. Flogel M,
    5. Lauc G
    . Fucosylation of IgG heavy chains is increased in rheumatoid arthritis. Clin Biochem 1999;32:605–8.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Flogel M,
    2. Lauc G,
    3. Gornik I,
    4. Macek B
    . Fucosylation and galactosylation of IgG heavy chains differ between acute and remission phases of juvenile chronic arthritis. Clin Chem Lab Med 1998;36:99–102.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Shields RL,
    2. Lai J,
    3. Keck R,
    4. O’Connell LY,
    5. Hong K,
    6. Meng YG,
    7. et al.
    Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fc-gamma RIII and antibody-dependent cellular toxicity. J Biol Chem 2002;277:26733–40.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Holland M,
    2. Takada K,
    3. Okumoto T,
    4. Takahashi N,
    5. Kato K,
    6. Adu D,
    7. et al.
    Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis. Clin Exp Immunol 2002;129:183–90.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Martin K,
    2. Talukder R,
    3. Hay FC,
    4. Axford JS
    . Characterization of changes in IgG associated oligosaccharide profiles in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis using fluorophore linked carbohydrate electrophoresis. J Rheumatol 2001;28:1531–6.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Shinzaki S,
    2. Iijima H,
    3. Nakagawa T,
    4. Egawa S,
    5. Nakajima S,
    6. Ishii S,
    7. et al.
    IgG oligosaccharide alterations are a novel diagnostic marker for disease activity and the clinical course of inflammatory bowel disease. Am J Gastroenterol 2008;103:1173–81.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

The Journal of Rheumatology
Vol. 39, Issue 3
1 Mar 2012
  • Table of Contents
  • Table of Contents (PDF)
  • Index by Author
  • Editorial Board (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about The Journal of Rheumatology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
IgG Glycosylation Changes and MBL2 Polymorphisms: Associations with Markers of Systemic Inflammation and Joint Destruction in Rheumatoid Arthritis
(Your Name) has forwarded a page to you from The Journal of Rheumatology
(Your Name) thought you would like to see this page from the The Journal of Rheumatology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
IgG Glycosylation Changes and MBL2 Polymorphisms: Associations with Markers of Systemic Inflammation and Joint Destruction in Rheumatoid Arthritis
LONE N. TROELSEN, SØREN JACOBSEN, JODIE L. ABRAHAMS, LOUISE ROYLE, PAULINE M. RUDD, EVA NARVESTAD, NIELS H. HEEGAARD, PETER GARRED
The Journal of Rheumatology Mar 2012, 39 (3) 463-469; DOI: 10.3899/jrheum.110584

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

 Request Permissions

Share
IgG Glycosylation Changes and MBL2 Polymorphisms: Associations with Markers of Systemic Inflammation and Joint Destruction in Rheumatoid Arthritis
LONE N. TROELSEN, SØREN JACOBSEN, JODIE L. ABRAHAMS, LOUISE ROYLE, PAULINE M. RUDD, EVA NARVESTAD, NIELS H. HEEGAARD, PETER GARRED
The Journal of Rheumatology Mar 2012, 39 (3) 463-469; DOI: 10.3899/jrheum.110584
del.icio.us logo Twitter logo Facebook logo  logo Mendeley logo
  • Tweet Widget
  •  logo
Bookmark this article

Jump to section

  • Article
    • Abstract
    • MATERIALS AND METHODS
    • RESULTS
    • DISCUSSION
    • Acknowledgment
    • Footnotes
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • References
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Long-Term Effectiveness and Safety of Denosumab for Osteoporosis in Patients With Rheumatic Diseases
  • Clinically Inactive Disease and Remission in Patients With Juvenile Idiopathic Arthritis Receiving Tofacitinib: Post Hoc Analysis of a Phase III Trial
  • Modifiable Lifestyle Factors, Genetic Susceptibility, and Incident Radiographic Axial Spondyloarthritis
Show more Articles

Similar Articles

Content

  • First Release
  • Current
  • Archives
  • Collections
  • Audiovisual Rheum
  • COVID-19 and Rheumatology

Resources

  • Guide for Authors
  • Submit Manuscript
  • Author Payment
  • Reviewers
  • Advertisers
  • Classified Ads
  • Reprints and Translations
  • Permissions
  • Meetings
  • FAQ
  • Policies

Subscribers

  • Subscription Information
  • Purchase Subscription
  • Your Account
  • Terms and Conditions

More

  • About Us
  • Contact Us
  • My Alerts
  • My Folders
  • Privacy/GDPR Policy
  • RSS Feeds
The Journal of Rheumatology
The content of this site is intended for health care professionals.
Copyright © 2025 by The Journal of Rheumatology Publishing Co. Ltd.
Print ISSN: 0315-162X; Online ISSN: 1499-2752
Powered by HighWire