Immunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulin
<p>The IgG Fc domain mediates a range of antibody effector functions, including antibody dependent cell-mediated cytotoxicity (ADCC), complement activation, phagocytosis, and the recently emerged general anti-inflammatory effect of immunoglobulin therapy (IVIg). The conserved N-glycan attached...
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| Iaith: | English |
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2013
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| _version_ | 1826315702034759680 |
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| author | Yu, X |
| author2 | Scanlan, C |
| author_facet | Scanlan, C Yu, X |
| author_sort | Yu, X |
| collection | OXFORD |
| description | <p>The IgG Fc domain mediates a range of antibody effector functions, including antibody dependent cell-mediated cytotoxicity (ADCC), complement activation, phagocytosis, and the recently emerged general anti-inflammatory effect of immunoglobulin therapy (IVIg). The conserved N-glycan attached to Fc N297 maintains the Fc structural integrity for the effector functions, while its glycoform is known to modulate the affinity for the Fc γ-receptors (FcγRs), complement, and the C-type lectin DC-SIGN. IgG Fc exhibits protein-directed glycosylation characterized by a series of biantennary complex type glycoforms, with a small population of sialylated species. The sialylated Fc has been proposed to bind DC-SIGN and initiate an anti-inflammatory signalling pathway. The restricted Fc glycan processing is partially attributed to the hydrophobic interaction between Fc glycan and the hydrophobic Fc protein backbone. Mutations within the hydrophobic Fc protein-glycan interface dramatically increases Fc glycan processing, while concomitantly decreases Fc affinity for the FcγRs. However, it is unclear whether this disrupted Fc-FcγR interaction was due to the increased terminal glycan processing, or the perturbed Fc protein-glycan interface. Here, the integrity of the Fc protein-glycan interface was demonstrated to be important in maintaining the productive Fc-FcγR interaction independently of glycoform. This glycoform-independent effect was exploited to generate novel inhibitory Fc variants. In addition, the interaction between sialylated IgG and the putative IVIg receptor DC-SIGN was re-evaluated. Analysis shows that IVIg binds DC-SIGN in a glycan-independent, Fab-mediated manner. Furthermore, the effect of IVIg sialylation on human antigen presenting cells was examined; evidence presented here indicate that IVIg deglycosylation, not desialylation, has an anti-inflammatory effect on human dendritic cells (DCs). These data suggest the need for a general re-evaluation of the current mechanistic model of anti-inflammatory IVIg.</p> |
| first_indexed | 2024-03-06T19:02:28Z |
| format | Thesis |
| id | oxford-uuid:140048b3-7cf4-4a30-932b-59c3e1d20272 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:30:53Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:140048b3-7cf4-4a30-932b-59c3e1d202722024-12-01T14:14:28ZImmunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulinThesishttp://purl.org/coar/resource_type/c_db06uuid:140048b3-7cf4-4a30-932b-59c3e1d20272ImmunologyBiophysicsMedical SciencesBiochemistryDendritic cell researchGlycobiologyChemical biologyBiologyEnglishOxford University Research Archive - Valet2013Yu, XScanlan, CCrispin, M<p>The IgG Fc domain mediates a range of antibody effector functions, including antibody dependent cell-mediated cytotoxicity (ADCC), complement activation, phagocytosis, and the recently emerged general anti-inflammatory effect of immunoglobulin therapy (IVIg). The conserved N-glycan attached to Fc N297 maintains the Fc structural integrity for the effector functions, while its glycoform is known to modulate the affinity for the Fc γ-receptors (FcγRs), complement, and the C-type lectin DC-SIGN. IgG Fc exhibits protein-directed glycosylation characterized by a series of biantennary complex type glycoforms, with a small population of sialylated species. The sialylated Fc has been proposed to bind DC-SIGN and initiate an anti-inflammatory signalling pathway. The restricted Fc glycan processing is partially attributed to the hydrophobic interaction between Fc glycan and the hydrophobic Fc protein backbone. Mutations within the hydrophobic Fc protein-glycan interface dramatically increases Fc glycan processing, while concomitantly decreases Fc affinity for the FcγRs. However, it is unclear whether this disrupted Fc-FcγR interaction was due to the increased terminal glycan processing, or the perturbed Fc protein-glycan interface. Here, the integrity of the Fc protein-glycan interface was demonstrated to be important in maintaining the productive Fc-FcγR interaction independently of glycoform. This glycoform-independent effect was exploited to generate novel inhibitory Fc variants. In addition, the interaction between sialylated IgG and the putative IVIg receptor DC-SIGN was re-evaluated. Analysis shows that IVIg binds DC-SIGN in a glycan-independent, Fab-mediated manner. Furthermore, the effect of IVIg sialylation on human antigen presenting cells was examined; evidence presented here indicate that IVIg deglycosylation, not desialylation, has an anti-inflammatory effect on human dendritic cells (DCs). These data suggest the need for a general re-evaluation of the current mechanistic model of anti-inflammatory IVIg.</p> |
| spellingShingle | Immunology Biophysics Medical Sciences Biochemistry Dendritic cell research Glycobiology Chemical biology Biology Yu, X Immunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulin |
| title | Immunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulin |
| title_full | Immunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulin |
| title_fullStr | Immunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulin |
| title_full_unstemmed | Immunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulin |
| title_short | Immunomodulatory properties of IgG glycosylation and the anti-inflammatory mechanism of intravenous immunoglobulin |
| title_sort | immunomodulatory properties of igg glycosylation and the anti inflammatory mechanism of intravenous immunoglobulin |
| topic | Immunology Biophysics Medical Sciences Biochemistry Dendritic cell research Glycobiology Chemical biology Biology |
| work_keys_str_mv | AT yux immunomodulatorypropertiesofiggglycosylationandtheantiinflammatorymechanismofintravenousimmunoglobulin |