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J Dent Res 84(10):897-901, 2005
© 2005 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Heterogeneity of IgG Glycosylation in Adult Periodontal Disease

J. Novak1,*, M. Tomana2, G.R. Shah3, R. Brown1, and J. Mestecky1,2

1 Departments of Microbiology-Box 1, 2 Medicine, and 3 Oral Diagnostics, University of Alabama at Birmingham, 845 19th Street South, Birmingham, AL 35294-2170;

* corresponding author, jannovak{at}uab.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Periodontal disease is a chronic inflammatory disease of bacterial etiology. In many other chronic inflammatory diseases, IgG glycans are galactose-deficient and thus capable of complement activation through the lectin pathway. In this study, we examined whether IgG in serum and gingival crevicular fluid, and IgG locally produced by plasma cells in gingiva of periodontal disease patients, display altered glycosylation. We developed a lectin-ELISA to measure levels of galactose-deficient IgG in the fluids and immunofluorescence staining to detect galactose-deficient IgG-producing cells in gingiva. Our results indicated higher levels of galactose-deficient IgG in sera and gingival crevicular fluid from periodontal disease patients, compared with levels in healthy controls. Furthermore, gingivae from periodontal disease patients exhibited infiltration of IgG-producing plasma cells; many of them contained galactose-deficient IgG in the cytoplasm. Analysis of our data suggests that IgG secreted by B-cells was aberrantly glycosylated, which resulted in the production of pro-inflammatory galactose-deficient IgG.

KEY WORDS: IgG • N-glycans • periodontal disease • galactose deficiency.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Antigens and bacterial products of Gram-negative bacteria associated with periodontal disease (Socransky et al., 1998) induce chronic inflammatory responses in the periodontium, ultimately resulting in the progressive loss of tooth support (for review, see Fujihashi et al., 1993; Kinane et al., 1999).

In many respects, periodontal disease shares some common features with other chronic inflammatory diseases, particularly with rheumatoid arthritis, including: production of IgM and IgA rheumatoid factor (Hirsch et al., 1989); infiltration of inflamed tissue with mainly IgG-secreting plasma cells (Ogawa et al., 1989); production of auto-antibodies to tissue components (collagen II in rheumatoid arthritis; collagens I and III in periodontal disease; Hirsch et al., 1988); similar cytokine profiles (Fujihashi et al., 1993; Pistoia, 1997); and increased levels of IL-6 (Fujihashi et al., 1993; Pistoia, 1997).

Extensive structural studies of IgG molecules produced at the site of chronic inflammation and detectable in the circulation revealed profound alterations in the glycan moieties. Specifically, deficiencies of some monosaccharides, especially galactose on IgG, have been described in human chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, tuberculosis, and infection with HIV (Mullinax and Mullinax, 1975; Parekh et al., 1985 , 1988; Tomana et al., 1988; Bodman et al., 1992; Tsuchiya et al., 1993; Rademacher et al., 1994; Tomana, 1996; Moore et al., 2005). IgG contains one complex-type oligosaccharide (Fig. 1AGo) per each heavy chain linked to the conserved glycosylation site on asparagine 297 within constant region domain 2, which presumably has a role in maintaining the three-dimensional structure of the Fc portion of IgG. In IgG with galactose-deficient glycans, the terminally exposed sugar molecule is N-acetylglucosamine. Analysis of experimental data has indicated that galactose-deficient IgG is pathogenic (Rademacher et al., 1994): Galactose-deficient IgG binds to the mannan-binding lectin and thus activates the complement cascade by the lectin pathway (Malhotra et al., 1995). Furthermore, glycans on IgG molecules affect binding and internalization by Fc receptors expressed on phagocytic cells (Krapp et al., 2003) and, thus, influence opsonization of antigens by phagocytosis.



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  		Figure 1. Structure of N-linked glycans of IgG and analyses of IgG galactose deficiency. (A) Example of complex type N-linked glycans. Abbreviations: N-acetylglucosamine (GlcNAc), galactose (Gal), sialic acid (SA), mannose (Man), fucose (Fuc), asparagine (Asn). Variably present saccharides are in parentheses. Fc region-associated glycans of IgG are usually not sialylated, and only some of them are fully galactosylated or with bisecting N-acetylglucosamine. Galactose-deficient IgG glycans are terminated by N-acetylglucosamine residues that react with PVL lectin, while fully galactosylated glycans do not react with PVL. (B) Correlation between PVL reactivity (OD 405 nm, 30 min) and gas-liquid monosaccharide composition (mannose/galactose ratio) of differently galactosylated purified IgGs. Pierson’s correlation coefficient, r = 0.73 (N = 18).

 
In this study, we examined whether IgG in the serum, gingival crevicular fluid, or IgG produced locally by plasma cells that infiltrate gingiva in periodontal disease display altered glycan moieties.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Controls
Serum samples were obtained from 14 adult periodontal patients (average age, 55 yrs; range, 38–70 yrs; five males and nine females) and 10 healthy controls (average age, 47 yrs; range, 34–54 yrs; six males and four females). The periodontal disease patients exhibited attachment loss and periodontal pockets of > 3.5 mm (ranging from 4 to 9 mm), and bleeding on probing. The control group consisted of patients with pocket depths between 0 and 3 mm, and no attachment loss or bleeding on probing. Samples of gingival crevicular fluid were collected with the use of Periopaper as described previously (Grbic et al., 1995). Gingiva- and periodontium-containing tissues removed from periodontal disease patients for therapeutic purposes were fixed (as described in Kilian et al., 1989) and used for staining. The study was approved by the Institutional Review Board; an informed written consent was obtained before any samples were collected.

ELISA
We used binding of Psathyrella velutina lectin (PVL) to examine galactose-deficiency of N-linked glycans on IgG molecules. PVL detects galactose-deficient N-linked glycans through their binding to terminal N-acetylglucosamine (Tsuchiya et al., 1993). IgG (or serum diluted 1:1000) was reduced, alkylated, and captured on protein-G-coated plates, and the presence of terminal N-acetylglucosamine was probed with biotin-labeled PVL. Simultaneously, IgG levels were also measured by ELISA; the relative N-acetylglucosamine content of IgG-containing samples was expressed as PVL/IgG ratio.

Gas-liquid Chromatography Analysis of IgG Monosaccharide Composition
The monosaccharides from purified IgG proteins were determined as trifluoroacetates of methyl-glycosides by gas chromatography, as described previously (Tomana et al., 1984). The analyses were performed with a Hewlett-Packard model 5890 series II gas chromatograph equipped with a 25-m fused silica (0.22-mm inner diameter) OV-1701 WCOT column and electron capture detector; GC ChemStation software (Agilent Technologies, Palo Alto, CA, USA) was used for acquisition of chromatographic data and peak integration. The galactose content in IgG was determined relative to that of mannose, since the latter was shown to be constant in patients with various autoimmune diseases and in normal healthy controls (Tomana et al., 1988). About 50 µg of each IgG was used for the analyses.

Immunofluorescence
Gingiva- and periodontium-containing tissues removed from periodontal disease patients for therapeutic purposes were examined by immunofluorescence microscopy. The tissue was stained with fluorescein isothiocyanate- (FITC) or tetramethylrhodamine isothiocyanate- (TRITC) labeled F(ab')2 fragments of antibodies recognizing human IgG, and with biotin-labeled PVL followed by avidin conjugated with 7-amino-4-methyl-coumarin-3-acetate (AMCA) for determination of the presence of IgG-producing cells and the production of galactose-deficient IgG. Tissue fixation and processing were conducted as previously described (Kilian et al., 1989). Control tissues included gingivae from patients who underwent crown-lengthening with no evidence of periodontal disease. The staining performed on such tissues showed the absence or scarcity of IgG-producing cells in healthy gingivae. In addition, all tissues were stained by hematoxylin-eosin so that the cell types present could be determined. Seven gingivae samples from periodontal disease patients and six gingivae samples from normal controls were used.

Statistical Analysis
Correlation coefficients (r) were calculated by means of the Microsoft Excel statistical package. Comparisons between group means were performed by Student’s t test. P values equal to or less than 0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Initially, we verified the ELISA method for detection of galactose-deficient IgG using biotin-labeled PVL (Tsuchiya et al., 1993). We used our collection of IgG preparations purified from sera of patients with rheumatoid arthritis, inflammatory bowel disease, and normal controls (Tomana, 1996; Tomana et al., 1988). These IgG preparations were analyzed by gas-liquid chromatography (galactose content expressed as mannose/galactose ratio) and by PVL-ELISA. Results of both of these methods correlated (correlation coefficient, r = 0.73; Fig. 1BGo).

PVL reactivity of IgG in sera from 14 periodontal disease patients and 10 healthy controls had mean OD values ± SD of 0.63 ± 0.32 and 0.25 ± 0.22, respectively (P = 0.0046; Fig. 2AGo). This result indicated that sera from periodontal disease patients contained more galactose-deficient IgG compared with that from normal healthy controls.



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  		Figure 2. Galactose deficiency of IgG in serum and gingival crevicular fluid of periodontal disease patients and controls. (A) PVL reactivity (OD at 405 nm after 2 hrs of incubation) of serum IgG from patients with periodontal disease (N = 14) and from healthy controls (N = 10). P = 0.0046. (B) IgG glycosylation (PVL index) in serum and gingival crevicular fluid (GCF) from periodontal patients (N = 7).

 
Furthermore, we determined the PVL reactivity of IgG present in gingival crevicular fluid and in the matching samples of sera. To compensate for different levels of IgG in the samples of gingival crevicular fluid, we expressed all values relative to the IgG amount as a PVL/IgG index (Fig. 2BGo). The results indicated the presence of galactose-deficient IgG in gingival crevicular fluid of the patients. When the gingival crevicular fluid and the matched serum samples were compared, two patterns emerged: One group of patients exhibited higher levels of galactose-deficient IgG in serum but lower levels of galactose-deficient IgG in gingival crevicular fluid, while the second group exhibited the reverse pattern. It has been shown that the humoral immune responses in the periodontium have contributions from both the mucosal and systemic compartments (Kinane et al., 1999). This is consistent with the study indicating a possible protective role of IgA in gingival crevicular fluid (Grbic et al., 1995). The latter report showed that the concentration of IgA negatively correlated with mean attachment level, mean probing depth, and mean bleeding on probing, the three major clinical measures of periodontal disease. Using the same samples in which we measured IgG and PVL/IgG index, we also determined the levels of IgA. When the results were analyzed, we found that the probing depth (ranging from 4 to 9 mm) correlated with the levels of the abnormally glycosylated IgG in gingival crevicular fluid (r = 0.52). Furthermore, we found a negative correlation between IgA levels and PVL/IgG index (r = 0.45) and a positive correlation between IgG:IgA ratio and PVL/IgG index (r = 0.46). Even with the small number of samples, these results together support the notion that the abnormally glycosylated IgG is present in gingival crevicular fluid from the periodontal disease patients with more severe disease.

Gingivae from periodontal disease patients with well-developed and uncontrolled disease contained infiltration of plasma cells, producing mostly IgG. To examine whether these IgG-producing cells secrete galactose-deficient IgG, we have used double-immunofluorescence with anti-IgG antibody and PVL. From the results of immunohistochemical staining, we concluded that a proportion of IgG-producing cells contained galactose-deficient IgG in the cytoplasm (Fig. 3Go).



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  		Figure 3. Paired immunofluorescence staining for IgG with FITC-conjugated (green) F(ab')2 fragment of anti-human IgG and galactose-deficient N-linked glycans disclosed by biotinylated PVL and AMCA-labeled avidin (blue) of gingivae from patients with advanced periodontal disease. The picture shows a representative example of inflamed periodontal disease tissue (N = 7). Most of the IgG-containing cells (green) co-stain for galactose-deficiency (blue). Arrows point to IgG-containing cells that do not stain with PVL. Bar size, 8 µm.

 
In conclusion, analysis of our data suggests a possibility that, in periodontal disease, as in other chronic inflammatory diseases, the terminal differentiation of B-cells is affected, resulting in the production of pro-inflammatory galactose-deficient IgG. Such IgG was present in gingival crevicular fluid, as well as in the circulation, of periodontal disease patients.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of these studies indicate that IgG present in the sera and gingivae from periodontal disease patients is deficient in galactose on N-linked glycans. Thus, in this respect, this IgG was analogous to that produced in other chronic inflammatory diseases of autoimmune character (such as rheumatoid arthritis), or induced by chronic microbial infections such as HIV (Mullinax and Mullinax, 1975; Parekh et al., 1985, 1988; Tomana et al., 1988; Bodman et al., 1992; Tsuchiya et al., 1993; Rademacher et al., 1994; Tomana, 1996; Moore et al., 2005).

A growing body of evidence indicates that glycan moieties on glycoproteins, including immunoglobulins, play an essential role in many biological processes and functions (Varki, 1993). For example, glycans on immunoglobulin molecules participate in binding to Fc receptors expressed on phagocytic cells (Monteiro et al., 1990; Leader et al., 1991), opsonization of antigens for phagocytosis, and activation of complement (Tao et al., 1993). These essential functions of immunoglobulin-associated glycans have been demonstrated by studies of immunoglobulin molecules modified by various glycosidases or chemical cleavages, replacement of asparagine with other amino acid residues by site-directed mutagenesis, or inhibitors of glycosylation (e.g., tunicamycin) in immunoglobulin-producing cells (Leader et al., 1991). Polymorphism of IgG glycosylation is associated with variable interactions with Fc{gamma} RIII receptor and activation of the complement cascade through the lectin pathway (Malhotra et al., 1995). The role of glycans in complement activation indicated that, in such molecules, N-acetylglucosamine, which becomes the terminal glycan in galactose-deficient IgG, binds mannan-binding lectin. In turn, this may result in local complement activation by complexes composed of tissue auto-antigens or microbial antigens (see below) and corresponding antibodies, all with inflammatory consequences. Importantly, IgA and IgG4 that normally do not activate complement become complement-binding isotypes when glycan moieties are altered (Parekh et al., 1985; Garred et al., 1989; Russell et al., 1997; Tao et al., 1993). Galactose-deficient IgG4 may, in tissues, activate complement, with all the resultant inflammatory consequences. Thus, the anti-inflammatory properties of IgA and IgG4, manifested by their ability to interfere with IgG1-, IgG2-, and IgG3-mediated complement activation, are lost due to their altered glycans (Russell et al., 1989, 1997).

In autoimmune diseases, such as rheumatoid arthritis, tissue components and cartilage collagen Type II, in particular, are the autoantigens recognized by galactose-deficient IgG molecules (Rademacher et al., 1994). We have demonstrated, in our earlier studies, that in periodontal disease, collagens Type I and III are recognized by locally produced IgG antibodies (Hirsch et al., 1988). Therefore, in addition to antigens derived from bacteria associated with periodontal disease, tissue autoantigens may also be targets of IgG antibodies that, in turn, activate, in the form of immune complexes, complement cascade with all its inflammatory sequelae and subsequent tissue damage.

Glycosylation of immunoglobulins is mediated by a large family of enzymes—glycosyltransferases—specific for individual carbohydrates (Schachter and Roseman, 1980). These enzymes catalyze the transfer of intracellularly activated monosaccharides (e.g., UDP-galactose) to suitable acceptors. The decreased levels of glycosyltransferases or their functional deficiency results in reduced or absent glycosylation of the acceptor—in this case, IgG molecules. Differentiation of B-cells is regulated by several cytokines, particularly IL-6 (Fujihashi et al., 1993; Pistoia, 1997), whose increased levels may result in decreased glycosylation. In view of the fact that high levels of IL-6 are produced by mononuclear cells isolated from the gingivae of patients with periodontal disease (Fujihashi et al., 1993), it is possible that, in addition to the stimulation of local B-cell differentiation into immunoglobulin-secreting plasma cells abundant in the inflamed gingiva (Kilian et al., 1989; McGhee et al., 1989; Ogawa et al., 1989), decreased galactosylation of IgG further enhances the inflammatory response.

Overall, these results suggest a possibility that, in periodontal disease, the terminal differentiation of B-cells is affected, resulting in the production of pro-inflammatory galactose-deficient IgG.


   ACKNOWLEDGMENTS
 
This work was supported by grant DE 13694 from the National Institutes of Health and by the UAB Center for Research in Oral Biology. We appreciate the assistance of Dr. Jeffcoat in obtaining the gingival tissue samples from periodontal disease patients.

Received December 9, 2004; Last revision April 15, 2005; Accepted June 29, 2005


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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