Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity

Quast, Isaak; Keller, Christian W.; Maurer, Michael; Giddens, John P.; Tackenberg, Björn; Wang, Lai-Xi; Münz, Christian; Nimmerjahn, Falk; Dalakas, Marinos C.; Lünemann, Jan D.

doi:10.1172/jci82695

Cited by 229 publications

(208 citation statements)

References 60 publications

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“…In contrast, FA2G2S1, the major sialylated glycan in IgG glycome, is decreasing with age [33], and it was also reported to be decreased in patients with systemic lupus erythematosus [34] and kidney disease [14]. Terminal α2,6-sialylation of IgG glycans decreases the ability of IgG to bind Fcγ receptors (FcγRs), which increases expression of inhibitory FcγRIIB and is anti-inflammatory [21,37]. However, these findings have not been confirmed in all studies [22,38,39].…”

Section: Discussionmentioning

confidence: 99%

Effects of statins on the immunoglobulin G glycome

Keser

Vučković

Barrios

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Statins are among the most widely prescribed medications worldwide and usually many individuals involved in clinical and population studies are on statin therapy. Immunoglobulin G (IgG) glycosylation has been associated with numerous cardiometabolic risk factors. Methods The aim of this study was to investigate the possible association of statin use with N-glycosylation of IgG. The association was analyzed in two large population cohorts (TwinsUK and KORA) using hydrophilic interaction liquid chromatography (HILIC-UPLC) in the TwinsUK cohort and reverse phase liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS) in the KORA cohort. Afterwards we investigated the same association for only one statin (rosuvastatin) in a subset of individuals from the randomized double-blind placebo-controlled JUPITER study using LC-ESI-MS for IgG glycome and HILIC-UPLC for total plasma N-glycome. Results In the TwinsUK population, the use of statins was associated with higher levels of core-fucosylated biantennary glycan structure with bisecting N-acetylglucosamine (FA2B) and lower levels of core-fucosylated biantennary digalactosylated monosialylated glycan structure (FA2G2S1). The association between statin use and FA2B was replicated in the KORA cohort. In the JUPITER trial we found no statistically significant differences between the randomly allocated placebo and rosuvastatin groups. Conclusions In the TwinsUK and KORA cohorts, statin use was associated with a small increase of pro-inflammatory IgG glycan, although this finding was not confirmed in a subset of participants from the JUPITER trial. General Significance Even if the association between IgG N-glycome and statins exists, it is not large enough to pose a problem for glycomic studies.

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Section: Discussionmentioning

confidence: 99%

Effects of statins on the immunoglobulin G glycome

Keser

Vučković

Barrios

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…For example, Quast and colleagues [72] showed that high levels of terminal sialic acid significantly impaired CDC activity mediated by rituximab.…”

Section: Enhancing Cdc Activitymentioning

confidence: 99%

Modulating Cytotoxic Effector Functions by Fc Engineering to Improve Cancer Therapy

Kellner

Otte

Cappuzzello

et al. 2017

Transfus Med Hemother

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In the last two decades, monoclonal antibodies have revolutionized the therapy of cancer patients. Although antibody therapy has continuously been improved, still a significant number of patients do not benefit from antibody therapy. Therefore, rational optimization of the antibody molecule by Fc engineering represents a major area of translational research to further improve this potent therapeutic option. Monoclonal antibodies are able to trigger a variety of effector mechanisms. Especially Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement- dependent cytotoxicity (CDC) are considered important in antibody therapy of cancer. Novel mechanistic insights into the action of monoclonal antibodies allowed the development of various Fc engineering approaches to modulate antibodies' effector functions. Strategies in modifying the Fc glycosylation profile (Fc glyco-engineering) or approaches in engineering the protein backbone (Fc protein engineering) have been intensively evaluated. In the current review, Fc engineering strategies resulting in improved ADCC, ADCP and CDC activity are summarized and discussed.

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“…Potential mechanisms include FcγR blocking [20], modulation of FcγR expression and signaling [21,22], increased autoantibody clearance by FcRn saturation [23], suppression of immunoglobulin production [24], modulation of antigen-presenting cell activation by induction of inhibitory FcγRIIB [25], and blockade of complement proteins [26,27]. Other potential mechanisms are induction of regulatory T cells by peptide sequences called Btregitopes^c ontained within the IgG constant regions [28], and inhibition of differentiation and maturation of dendritic cells [29].…”

Section: Fc-mediated Mechanismsmentioning

confidence: 99%

Efficacy of Intravenous Immunoglobulin in Neurological Diseases

2016

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Owing to its anti-inflammatory efficacy in various autoimmune disease conditions, intravenous immunoglobulin (IVIG)-pooled IgG obtained from the plasma of several thousands individuals-has been used for nearly three decades and is proving to be efficient in a growing number of neurological diseases. IVIG therapy has been firmly established for the treatment of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy, either as first-line therapy or adjunctive treatment. IVIG is also recommended as rescue therapy in patients with worsening myasthenia gravis and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. Subcutaneous rather than intravenous administration of IgG is gaining momentum because of its effectiveness in patients with primary immunodeficiency and the ease with which it can be administered independently from hospital-based infusions. The demand for IVIG therapy is growing, resulting in rising costs and supply shortages. Strategies to replace IVIG with recombinant products have been developed based on proposed mechanisms that confer the anti-inflammatory activity of IVIG, but their efficacy has not been tested in clinical trials. This review covers new developments in the immunobiology and clinical applications of IVIG in neurological diseases.

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Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity

Cited by 229 publications

References 60 publications

Effects of statins on the immunoglobulin G glycome

Effects of statins on the immunoglobulin G glycome

Modulating Cytotoxic Effector Functions by Fc Engineering to Improve Cancer Therapy

Efficacy of Intravenous Immunoglobulin in Neurological Diseases

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