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. 2008;10(5):R110.
doi: 10.1186/ar2507. Epub 2008 Sep 12.

Natural Autoantibodies Reactive With Glycosaminoglycans in Rheumatoid Arthritis

Free PMC article

Natural Autoantibodies Reactive With Glycosaminoglycans in Rheumatoid Arthritis

Bence György et al. Arthritis Res Ther. .
Free PMC article


Introduction: Although natural autoantibodies make up the majority of circulating immunoglobulins and are also present in high numbers in therapeutically used intravenous immunoglobulin preparations, they have received little attention and their precise role remains largely unknown. An increasing awareness of the importance of posttranslational autoantigen modifications and glycobiology led us to explore carbohydrate-reactive natural autoantibodies in patients with rheumatoid arthritis. This study examined systematic antibodies reactive to glycosaminoglycans (GAGs), the carbohydrate components of proteoglycans that are released in large amounts from degrading cartilage.

Methods: To measure antibodies reactive to six different types of GAGs, a specialised ELISA was used in which the carbohydrates were covalently linked to the plastic surface through a 2 nm spacer. Sera from rheumatoid arthritis patients (n = 66), umbilical cord serum samples (n = 11) and adult controls (n = 54) were studied. In order to explore cross-reactivity with microbial antigens, bacterial peptidoglycans and fungal polysaccharides were used. Sera and synovial fluid samples were also tested using a GlycoChip carbohydrate array to characterise individual carbohydrate recognition patterns. We followed a multistep statistical screening strategy for screening GAG-reactive antibodies as predictive disease markers.

Results: While anti-GAG antibodies were absent in the umbilical cord sera, they were readily detectable in adult controls and were significantly elevated in patients with rheumatoid arthritis (p < 0.001). Anti-GAG antibodies showed significant cross-reactivity among different types of GAGs. They also reacted with bacterial peptidoglycans and fungal polysaccharides. Interestingly, anti-chondroitin sulphate C IgM antibody levels showed inverse correlation both with the Disease Activity Score (DAS) 28 scores and C-reactive protein (CRP) levels in rheumatoid arthritis.

Conclusion: The highly abundant and cross-reactive, GAG-specific natural autoantibodies in serum may serve as novel disease-state markers in patients with rheumatoid arthritis.


Figure 1
Figure 1
Correlation between serum and synovial fluid anti-glycosaminoglycan (GAG) IgM and IgG antibodies in rheumatoid arthritis (RA). Note the strong and statistically significant correlation (p < 0.001) between the corresponding IgM anti-GAG concentrations in serum and synovial fluid samples. Such a relation could not be demonstrated for IgG antibodies (r = 0.13, N.S).
Figure 2
Figure 2
Scatter plot of anti-glycosaminoglycan (GAG) antibody concentrations. Log-transformed antibody concentrations were plotted against each other. Figure 2 suggests that there is a strong relation between anti-GAG antibody concentrations, particularly among IgM molecules. This observation has been confirmed by detailed statistical analysis, and the lowest value of the correlation coefficients between anti-GAG IgM antibodies was 0.86. The concentrations are expressed in μg/mL.
Figure 3
Figure 3
Correlation of anti-chondroitin sulphate C IgM levels with the disease and activity markers in rheumatoid arthritis. (a) Box plots of anti-chondroitin sulphate (CS) C IgM concentrations groups of controls and patients with rheumatoid arthritis (RA). The logarithm of the anti-CSC IgM concentration is plotted. The lines inside the boxes denote the medians. The boxes mark the interval between the 25th and 75th percentiles. The ends of the vertical lines or whiskers indicate the minimum and maximum data values, unless outliers are present in which case the whiskers extend to a maximum of 1.5 times the interquartile range. The difference between the controls (n = 55) and RA patients (n = 66) is statistically significant (p < 0.02, F-test). (b) Box plots of anti-CSC IgM concentrations in groups of controls and the patients with RA. Patients are stratified according to disease activitity scores (DAS) 28. Patients classified to DAS 1 group (n = 6) have significantly higher anti-CSC IgM concentrations compared with controls and to patients in the DAS 2 (n = 22) and 3 (n = 18) categories. No other significant differences have been found (p < 0.05, post-hoc Tukey's test). Result suggests that anti-CSC IgM is not a disease, but a state dependent marker. (c) Comparison of C-reactive protein (CRP) levels in patients according to their DAS scores. On the vertical axis the logarithm of CRP concentration is plotted. The only significant difference was found between groups DAS 1 and 3 (p < 0.05, post-hoc Tukey's test). (d) Box plots of anti-CSC IgM concentrations in groups of controls and patients with RA. Patients were stratified according to their CRP values into three subgroups: those having low, moderate or high CRP values (n = 17, n = 16 and n = 16, respectively). The anti-CSC IgM titre decreases when CRP concentration increases; the difference between the low and high CRP group is statistically significant (p < 0.05, post-hoc Tukey's test).
Figure 4
Figure 4
Detection of anti-glycosaminoglycan (GAG) antibody binding to the extracellular matrix of hyaline cartilage. Microphotograph (a) shows the binding of rheumatoid arthritis (RA) serum-derived antibodies to human cartilage. The reactivity could be inhibited by pre-incubation of the serum sample with chondroitin sulphate (CS) C. (b) is using 2 mg/ml CSC; (c) is using 4 mg/ml CSC as an inhibitor). Magnification: 100×

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