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Proc Natl Acad Sci U S A. Sep 30, 2008; 105(39): 15005–15009.
Published online Sep 24, 2008. doi:  10.1073/pnas.0808248105
PMCID: PMC2567483
Immunology

In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner

Abstract

IgG antibodies are potent inducers of proinflammatory responses. During autoimmune diseases such as arthritis and systemic lupus erythematosus, IgG autoantibodies are responsible for the chronic inflammation and destruction of healthy tissues by cross-linking Fc receptors on innate immune effector cells. The sugar moiety attached to the asparagine-297 residue in the constant domain of the antibody is critical for the overall structure and function of the molecule. Removal of this sugar domain leads to the loss of the proinflammatory activity, suggesting that in vivo modulation of antibody glycosylation might be a strategy to interfere with autoimmune processes. In this work, we investigated whether removal of the majority of the IgG-associated sugar domain by endoglycosidase S (EndoS) from Streptococcus pyogenes is able to interfere with autoimmune inflammation. We demonstrate that EndoS injection efficiently removes the IgG-associated sugar domain in vivo and interferes with autoantibody-mediated proinflammatory processes in a variety of autoimmune models. Importantly, however, we observed a differential impact of EndoS-mediated sugar side chain hydrolysis on IgG activity depending on the individual IgG subclass.

Keywords: autoantibody, endoglycosidase, Fc-receptor, immunotherapy

IgG antibodies play a crucial role in chronic inflammatory processes resulting in the destruction of healthy tissues during autoimmune diseases. A variety of studies have demonstrated the exclusive role of cellular receptors for the IgG constant domain (Fcγ receptors, FcγR) as the central mediators of autoantibody-triggered tissue inflammation (1, 2). In mice, the family of FcγRs consists of three activating (FcγRI, FcγRIII, FcγRIV) and one inhibitory (FcγRIIB) molecule that are expressed in varying combinations on virtually all innate immune effector cells, B cells, and dendritic cells (1). With the exception of NK cells, activating and inhibitory receptors are coexpressed, thereby setting a threshold for effector cell activation and downstream responses such as cell degranulation, phagocytosis, release of proinflammatory mediators, and antibody-dependent cellular cytotoxicity reactions. Several studies have demonstrated that the sugar domain attached to the asparagine-297 residue (Asn-297) in the CH2 domain of the antibody Fc portion is essential for maintaining the IgG antibody in a functional state (3). Removing the sugar moiety by either replacing the Asn-297 residue with an alanine or treating antibodies with PNGaseF results in a dramatic reduction of the affinity for cellular FcγRs and a loss in proinflammatory activity (46). Thus, interfering with antibody glycosylation in vivo might be a promising strategy to dampen autoantibody-induced tissue destruction and chronic inflammation. A prerequisite for such an approach, however, would be to target IgG antibodies specifically because virtually all cells and many serum proteins carry similar sugar structures, which would make it rather unlikely for non-IgG-specific enzymes to achieve a high level of IgG deglycosylation.

Recently, an endoglycosidase (EndoS) isolated from Streptococcus pyogenes was shown to cleave specifically the sugar moiety of IgG and not of IgM Ig isotypes, thus representing an interesting molecular tool to modulate IgG glycosylation in vivo (710). In contrast to PNGaseF, this enzyme does not remove the entire sugar moiety but keeps one N-acetylglucosamine (GlcNAc) of the core sugar structure and its branching fucose residue that is present in the majority of the serum IgG pool. In our previous studies, we were able to show that treatment of mouse and human IgG subclasses with EndoS in vitro results in a severely reduced affinity to cellular FcγRs (7, 10). Injection of EndoS-treated autoantibody preparations generated in rabbits resulted in a dramatic reduction of antibody activity in vivo, further supporting the notion that cellular FcγRs are the crucial mediators of antibody activity (9). Importantly, however, the delicate regulation of IgG activity by cellular FcγRs is not recapitulated precisely when using IgG preparations from other species. It is well established that the different IgG subclasses have a differential activity because of the selective interaction with specific activating and inhibitory FcγRs (1, 1113). Similarly, certain changes in antibody glycosylation, such as the absence of branching fucose residues, have been shown to affect selectively the interaction with human FcγRIIIA and mouse FcγRIV (13, 14).

Using a variety of murine autoimmune model systems and autoantibody subclass switch variants we show that EndoS efficiently hydrolyzes the sugar moiety of all IgG subclasses and is a potent therapeutic tool to interfere with autoantibody-induced tissue inflammation. Interestingly, the effect of EndoS-mediated hydrolysis of the IgG-associated sugar moiety shows subclass-specific effects, with IgG1 and IgG2b variants being more affected than IgG2a.

Results and Discussion

Hydrolysis of the IgG Glycan Moiety in Mouse Serum.

EndoS cleaves the sugar moiety of IgG after the first GlcNAc, leaving only the GlcNAc with or without a branching fucose residue (Fig. 1A). We and others have shown that EndoS efficiently hydrolyzes the IgG-associated sugar moiety in human and rabbit serum and on purified antibodies (7, 9, 10). Because the focus of this work was to investigate the effect of EndoS application in mouse in vivo models of induced and established autoimmune disease, we first set out to identify the conditions for optimal IgG glycan hydrolysis. As shown in Fig. 1B, treating mice in vivo with different amounts of purified EndoS resulted in a rapid and complete hydrolysis of the IgG associated sugar moiety after 45 min as determined by lectin blot analysis with Lens culinaris agglutinin (LCA). Injection of as few as 10 μg of purified EndoS was sufficient to induce an efficient removal of the sugar moiety of serum IgG (Fig. 1B). Of great importance for the use of EndoS as an antiinflammatory agent is the duration of the response and how fast the deglycosylated IgG is replaced by newly made immunoglobulins. For this, we followed the levels of IgG glycosylation for 2 weeks after treating mice with one single dose of 10 μg of EndoS. Consistent with the serum half-life of IgG, which is in the range of 8–12 days, LCA-positive serum IgG reappeared after 1 week and reached normal levels ≈2 weeks after EndoS injection (15).

Fig. 1.
EndoS-mediated hydrolysis of the IgG-associated glycan moiety in mice. (A) Shown is the fully processed Asn-297 attached sugar moiety of IgG. EndoS cleaves after the first GlcNAc, resulting in the generation of a minimal sugar moiety containing only one ...

IgG Subclass-Specific Effects of EndoS-Mediated Glycan Hydrolysis.

Our previous experiments showed that EndoS-mediated hydrolysis of the IgG-associated sugar moiety resulted in a strong reduction of the affinity for cellular FcγRs. Interestingly, however, some of the mouse and human IgG subclasses, such as mouse IgG2a and human IgG2, still showed significant affinities for activating FcγRs (7, 10). This important point remained open in our earlier studies because we used an arthritis model system in which the induction of autoimmune disease was crucially dependent on coinjection of active IgG2a and IgG2b subclasses specific for type II collagen (16). Injection of the individual IgG subclasses is not sufficient to induce disease in this model, indicating that we could not differentiate whether the function of only one (IgG2a or IgG2b) or both IgG subclasses was abrogated in our previous study. To analyze this in detail, we turned to a model of antibody-induced thrombocytopenia (ITP). In this model, injection of small amounts of individual IgG subclass variants of the platelet-specific 6A6 antibody results in a rapid induction of thrombocytopenia in a subclass specific manner within 4 h (13, 17). The IgG3 switch variant shows no activity in this model and was therefore not investigated in this work. As before, incubation of the different 6A6 subclass variants with EndoS resulted in an efficient hydrolysis of the Fc-associated sugar moiety (Fig. 2A). Upon injection of the EndoS-treated or untreated IgG subclasses, however, there was a differential impact of EndoS treatment with respect to the different IgG subclasses in vivo (Fig. 2B). Whereas the capacity of IgG1 and IgG2b to deplete 50% or 80% of platelets within 4 h was basically abrogated, IgG2a retained its activity, indicating that even this minimal sugar moiety consisting of one GlcNAc and one branching fucose residue (Fig. 1A) is sufficient to keep this IgG subclass in a functional state. These results are consistent with our previous affinity measurements in which IgG2a retained its affinity for the activating FcγRIV, which is crucially involved in mediating the effects of this subclass in this model system (10, 13, 17). To investigate whether IgG2a molecules with this minimal sugar moiety are still dependent on activating FcγRs, we injected wild-type C57BL/6 or FcR γ-deficient mice (γ-chain−/−), lacking all activating FcγRs, with untreated or EndoS-treated 6A6-IgG2a preparations. As shown in Fig. 2C, the activity of EndoS-treated IgG2a was still fully dependent on activating FcγRs, consistent with our previous results (13). These findings have important implications for the use of EndoS as a therapeutic agent in vivo because only autoimmune diseases with autoantibodies of the IgG1 and IgG2b subclass will be functionally impaired after EndoS treatment. Interestingly, we have observed similar selective effects of EndoS treatment on human IgG subclasses (7). With respect to the defense against infections with S. pyogenes, it is quite interesting that the most potent proinflammatory IgG subclass that has been shown to be crucial for the clearance of viral and bacterial infections remains functional in the presence of pathogen-derived IgG sugar moiety-hydrolyzing enzymes such as EndoS (18, 19). Thus, using EndoS in contrast to other immunosuppressive drugs will not completely impair humoral defense mechanisms and therefore might result in a reduced danger for opportunistic infections. However, autoimmune diseases in which IgG subclasses dominate that are not impaired by EndoS-mediated sugar moiety hydrolysis might show only partial therapeutic effects. In human lupus, for example, autoantibodies of the IgG1 and IgG3 subclass seem to predominate, which might predict a good response to EndoS therapy (20, 21). Importantly, however, a rise of anti-nucleohistone antibodies of the IgG2 subclass preceded renal relapses, and all IgG subclasses were present in kidney biopsies, suggesting that autoantibody-mediated kidney inflammation might show a partial resistance to EndoS therapy (22).

Fig. 2.
IgG subclass-specific effects of EndoS-mediated hydrolysis of the IgG-associated sugar side chain. (A) IgG subclass switch variants of the platelet-specific 6A6 antibody were digested with EndoS and analyzed for the removal of the IgG-associated sugar ...

Impact of IgG Glycan Hydrolysis in Serum Transfer-Induced Arthritis.

Although the use of purified IgG autoantibody preparations is essential to analyze subclass-specific effects, a therapeutically more relevant situation is the presence of minor levels of autoantibodies in an excess of serum Ig molecules. To analyze this we turned to a well described model of serum transfer arthritis (23). In this model, injection of serum from arthritogenic K/BxN mice into wild-type C57BL/6 mice results in a rapid and transient development of clinical signs of arthritis (23, 24). Mice deficient in FcγRIII are largely resistant to this form of arthritis, consistent with the dominant role of autoantibodies of the IgG1 subclass in this model. Because EndoS treatment efficiently interfered with the activity of IgG1 in the ITP model (Fig. 2), we treated whole K/BxN serum with EndoS, which resulted in an efficient hydrolysis of the IgG-associated sugar moiety (Fig. 3A). Injection of this serum preparation led to a significant reduction in joint swelling and the recruitment of innate immune effector cells (Fig. 3 B–D). Nonetheless, we did not observe a complete block with respect to the recruitment of inflammatory effector cells and bone erosion, suggesting that either some minor level of autoantibodies was not hydrolyzed by EndoS or other subclasses such as IgG2a would cause this reduced level of pathology. Indeed, deletion of FcγRIII in contrast to functional impairment of all activating FcγRs by using the FcR γ-chain-knockout animals resulted in some residual ankle swelling (24).

Fig. 3.
Effect of EndoS treatment on serum transfer arthritis. (A) Serum from K/BxN mice was incubated with EndoS, and the efficiency of EndoS-mediated removal of the IgG-associated sugar moiety was analyzed by lectin blotting with LCA after purification of IgG ...

Treatment of Established Autoimmune Disease in BXSB Mice.

Although these results clearly demonstrate the capacity of EndoS as a therapeutic agent, a more clinically relevant situation would be the treatment of established autoimmune disease. Therefore, we investigated the effects of EndoS treatment in male BXSB mice, which spontaneously develop a lupus-like disease with the appearance of autoantibodies, severe glomerulonephritis, and a reduced life span (25, 26). We first addressed which IgG subclasses dominated the autoimmune response in BXSB mice. Using a panel of mouse IgG subclass-specific antibodies, we observed that autoantibodies of the IgG2b subclass were the most abundant as determined by ELISA and anti-nuclear antibody (ANA) analyses starting from 16 to 24 weeks of age, followed by a lower level of autoantibodies of the IgG2a subclass (Fig. 4). Therefore, we started treating the mice with a first injection of 10 μg of purified EndoS at 18 weeks of age followed by an additional injection 2 months later. As before, this treatment resulted in an efficient hydrolysis of the sugar moiety of serum IgG but not IgM (Fig. 5A). As shown in Fig. 5 B and C, EndoS treatment did not interfere with the production of anti-dsDNA or ANA-specific autoantibodies, and mice showed either constant or sometimes slightly increasing autoantibody levels during the course of treatment. In contrast, none of the untreated mice survived the presence of such high autoantibody levels longer than 35 weeks (Fig. 5D).

Fig. 4.
Appearance of autoreactive IgG subclasses in BXSB mice. (A) Serum of BXSB mice at 16 or 24 weeks of age was analyzed for the presence of autoantibodies with specificity for dsDNA. (B) The presence of anti-nuclear antibodies of the IgG1 and IgG2b subclasses ...
Fig. 5.
Treatment of autoimmune disease in BXSB mice. (A) Serum IgG and IgM of BXSB mice before (T0) and 24 h after (T24) injection with 10 μg of EndoS was quantified for the presence of the intact IgG sugar moiety by lectin blotting with LCA. (B and ...

Consistent with this observation, blood urea nitrogen levels as a marker for kidney function remained low in EndoS-treated mice even in the presence of high levels of autoantibodies, suggesting that EndoS-mediated hydrolysis of the IgG-associated sugar domain limits the interaction of autoantibodies with cellular FcγRs (data not shown). With respect to overall survival, the control mice rapidly died after 20 weeks of age, with 80% of the mice being dead after 30 weeks. In contrast, mice treated only twice with EndoS survived much longer, with all mice being alive at 30 weeks of age. After the abrogation of treatment the mice started succumbing to disease although 40% of the animals were still alive after 55 weeks of age. Interestingly, BXSB mice deficient in the common FcR γ-chain (BXSB-γ−/−), which lack all functional activating FcγRs and therefore represent the maximal effects that can be achieved by interfering with antibody–FcγR interactions, showed a similar survival pattern, with the first mice dying at 30 weeks of age (27).

Taking into consideration that EndoS injection results in an only transient removal of the IgG sugar moiety, it might be possible that other effects beyond the interference of IgG–FcγR interactions contribute to the observed antiinflammatory phenotype. Possible explanations include a time window between 18 and 26 weeks of age in which interference with autoantibody-mediated inflammation results in long-term effects. Thus, highly pathogenic autoantibody species might be produced at this stage, whereas later during life other specificities with a lower pathogenic potential dominate. Indeed, we have observed a change in autoantibody specificities as determined by ANA analysis depending on the age of the animals (Fig. 5B). Moreover, EndoS treatment might interfere with the functional activity of cell surface IgG on memory B cells and plasma blasts. Future studies will be necessary to address this point in greater detail.

A potential drawback of any foreign enzyme that is administered as a therapeutic agent is the development of neutralizing antibodies by the host that might interfere with protein activity. In the BXSB model, two i.v. injections of 10 μg of recombinant EndoS were not sufficient to induce a significant IgG response against EndoS, although a low-level IgM response could be detected (data not shown). Importantly, it was shown in previous studies that these anti-EndoS antibodies did not interfere with enzymatic activity, consistent with the results of our work (9).

Taken together, the use of pathogen-derived immunomodulatory molecules holds great promise for future applications in human therapy. Besides EndoS, another enzyme (IdeS) from S. pyogenes was recently used successfully to interfere with autoantibody-induced tissue inflammation (28). In contrast to the modulation of the sugar moiety by EndoS, the protease IdeS is a cysteine endopeptidase that dissociates IgG it into one F(ab′)2 and two monomeric Fc fragments thereby uncoupling innate from adaptive immune responses (2830). Despite the foreign nature and potential immunogenicity of these molecules, their use as first-line therapies should be very useful, and approaches aiming at a reduction of their immunogenicity will further increase their potential applicability in humans.

Materials and Methods

Mice.

C57BL/6 and BXSB mice were purchased from the Jackson Laboratory. FcRγ−/− mice (γ−/−) were generated in Jeffrey Ravetch's laboratory and backcrossed for 12 generations to the C57BL/6 background. KRN TCR transgenic mice on a C57BL/6 background (K/B) were gifts from D. Mathis and C. Benoist (Harvard Medical School, Boston, MA) and were bred to NOD mice to generate K/BxN mice. Female mice at 6–12 weeks of age were used for all experiments and maintained at the animal facilities of the University of Erlangen and the Rockefeller University in New York. All experiments were done in compliance with federal laws and institutional guidelines.

Antibodies and Reagents.

6A6 antibody switch variants were produced by transient transfection of 293T cells followed by purification via protein G as described in ref. 17. Similarly, recombinant EndoS was produced in Escherichia coli and purified via a GST affinity tag as described in ref. 31. LCA was obtained from Vector Laboratories and used according the manufacturer's instructions. Hep2 cell-coated slides were obtained from Bion, incubated with mouse serum (1:100), and developed as suggested by the manufacturer.

EndoS Treatment of Antibodies and Serum.

For all experiments, recombinant EndoS was used. For in vitro digestions, 200 μg of purified 6A6 antibodies was incubated with 1 μg of EndoS in PBS at 37°C for at least 5 h. Alternatively, 200 μl of mouse serum was incubated with 1 μg of EndoS under the same conditions. For in vivo applications, mice were injected with different amounts of purified EndoS in 200 μl of PBS into the tail vein. The efficiency of EndoS treatment was analyzed by lectin blotting with LCA as described.

ITP Model.

ITP was induced by i.v. injection of 4 μg of untreated or EndoS-treated 6A6 IgG subclass switch variants as described (13, 17). Platelet counts before and 4 h after injection were determined by blood collection (40 μl) from the retroorbital plexus and measuring platelet counts of a 1:10 dilution in PBS and 5% BSA in an Advia 120 hematology system (Bayer).

Serum Transfer, Arthritis Scoring, and Histology.

Serum was prepared as described in ref. 24. Briefly, serum was separated from blood collected from the K/BxN mice (6–12 weeks old). Serum collected over several weeks was pooled and frozen in aliquots. Arthritis was induced by one i.v. injection of 200 μl of K/BxN serum. Alternatively, serum was pretreated with EndoS (1 μg for 200 μl of serum) for 4 h at 37°C. Arthritis was scored by clinical examination, and the index of all four paws was added: 0 (unaffected), 1 (swelling of one joint), 2 (swelling of more than one joint), and 3 (severe swelling of the entire paw). For histological examination, ankle joints were fixed in 10% formalin, decalcified for 48 h in Decal solution, and embedded in paraffin. Four-micrometer sections were stained with hematoxylin/eosin.

Lectin Blotting.

The indicated amounts of 6A6 antibody glycovariants or purified IgG from K/BxN, BXSB, or C57BL/6 serum untreated or treated with EndoS were resolved by SDS/PAGE using 10% polyacrylamide gels under reducing conditions. Proteins were transferred to a PVDF membrane (Millipore), blocked with Western blocking reagent (Roche), followed by incubation with biotinylated LCA (4 μg/ml, Vector Laboratories) and an alkaline phosphatase-conjugated goat anti-biotin antibody (Sigma). Bound antibody was visualized with 4-nitro blue tetrazolium chloride/5-bromo-4-chloro-3-indolyl phosphate (Roche).

Statistical Analysis.

Statistical differences of clinical scores were calculated with the Mann–Whitney U test. All other statistical differences were determined with Student's t test. A P value <0.05 was considered significant.

Acknowledgments.

We are grateful to Stephan von Hoersten for access to the Advia Hematology System and to Diane Mathis and Christophe Benoist for sharing K/B mice. Melissa Woigk provided expert technical assistance. This work was supported by grants from the German Research Foundation (DFG) and the Bayerisches Genomforschungsnetzwerk (BayGene) (to F.N.), the Emmy-Noether Program of the DFG (to D.D.), the National Institutes of Health (to J.V.R.), and the Swedish Research Council Project 2005-4791 and Assistant Professorship (to M.C.).

Footnotes

The authors declare no conflict of interest.

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