Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1

Karsten, Christian M.; Pandey, Manoj Kumar; Figge, Julia; Kilchenstein, Regina; Taylor, Philip Russel; Rosas, Marcela; McDonald, Jacqueline U.; Orr, Selinda J.; Berger, Markus; Petzold, Dominique; Blanchard, Véronique; Winkler, André; Hess, Constanze; Reid, Delyth M.; Majoul, Irina; Strait, Richard T.; Harris, Nathaniel; Köhl, Gabriele; Wex, Eva; Ludwig, Ralf J.; Zillikens, Detlef; Nimmerjahn, Falk; Finkelman, Fred D.; Brown, Gordon D.; Ehlers, Marc; Köhl, Jörg

doi:10.1038/nm.2862

Cited by 404 publications

(387 citation statements)

References 40 publications

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“…These data suggest FcgRIIb may be interacting with an alternative receptor on mesangial cells. For instance, a negative regulatory interaction between FcgRIIb and the C5a receptor has been implicated in a recently published study (24).…”

Section: Discussionmentioning

confidence: 98%

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

Sharp

Martín-Ramírez

Mangsbo

et al. 2013

The Journal of Immunology

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FcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the FcγRIIb-knockout phenotype by inducing NTN in mice with a deficiency of FcγRIIb on either B cells alone (FcγRIIBfl/fl/CD19Cre+) or myeloid cells (FcγRIIBfl/fl/CEBPαCre+). Deletion of FcγRIIb from B cells did not increase susceptibility to NTN, compared with wild-type (WT) mice, despite higher Ab titers in the FcγRIIBfl/fl/CD19Cre+ mice compared with the WT littermate controls. In contrast, mice lacking FcγRIIb on myeloid cells had exacerbated disease as measured by increased glomerular thrombosis, glomerular crescents, albuminuria, serum urea, and glomerular neutrophil infiltration when compared with WT littermate controls. The role for FcγRIIb expression on radioresistant intrinsic renal cells in the protection from NTN was then investigated using bone marrow chimeric mice. FcγRIIb−/− mice transplanted with FcγRIIb−/− bone marrow were more susceptible to NTN than WT mice transplanted with FcγRIIb−/− bone marrow, indicating that the presence of WT intrinsic renal cells protects from NTN. These results demonstrate that FcγRIIb on myeloid cells plays a major role in protection from NTN, and therefore, augmentation of FcγRIIb on these cells could be a therapeutic target in human Ab-mediated glomerulonephritis. Where there was a lack of FcγRIIb on circulating myeloid cells, expression of FcγRIIb on intrinsic renal cells provided an additional level of protection from Ab-mediated glomerulonephritis.

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Section: Discussionmentioning

confidence: 98%

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

Sharp

Martín-Ramírez

Mangsbo

et al. 2013

The Journal of Immunology

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“…Since then, patient studies support the notion that IgG glycosylation directly impacts function. For autoimmunity, terminal galactosylation (27) and terminal sialylation (2-4, 6) are now established factors in immune modulation, whereas fucosylation has been shown to correlate with antibody-dependent cell-mediated viral inhibition (ADCVI) activity in the context of HIV infection (28,29) as well as antibody-dependent cellular cytotoxicity (ADCC) in vitro (30). For ADCC, structural rearrangements associated with the presence of fucose within the Fc domain appear to account for the functional shift (31), but it remains unclear how fucosylation translates into differential ADCVI activity.…”

Section: Discussionmentioning

confidence: 99%

B-cell–independent sialylation of IgG

Jones

Oswald

Joshi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

107

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IgG carrying terminal α2,6-linked sialic acids added to conserved N-glycans within the Fc domain by the sialyltransferase ST6Gal1 accounts for the anti-inflammatory effects of large-dose i.v. Ig (IVIg) in autoimmunity. Here, B-cell-specific ablation of ST6Gal1 in mice revealed that IgG sialylation can occur in the extracellular environment of the bloodstream independently of the B-cell secretory pathway. We also discovered that secreted ST6Gal1 is produced by cells lining central veins in the liver and that IgG sialylation is powered by serum-localized nucleotide sugar donor CMP-sialic acid that is at least partially derived from degranulating platelets. Thus, antibody-secreting cells do not exclusively control the sialylationdependent anti-inflammatory function of IgG. Rather, IgG sialylation can be regulated by the liver and platelets through the corresponding release of enzyme and sugar donor into the cardiovascular circulation.W hile en route to the plasma membrane as integral membrane proteins or for secretion, glycoproteins exiting the endoplasmic reticulum traverse the cis-, medial-, and trans-Golgi apparatus where the associated N-linked glycans are remodeled into their final form. This classically defined secretory pathway dictates that the glycoform of all glycoproteins produced by a cell is largely determined by the cohort of enzymes within the Golgi and the metabolic circumstances of that specific cell.Protein glycosylation is known to play fundamental roles in all aspects of biology, but has recently gained significant attention in immunology. When administered at high doses, i.v. Ig (IVIg) is an effective anti-inflammatory treatment for autoimmune patients (1). In 2006, it was discovered that the ∼10% of IgG molecules that carry α2,6-linked sialic acids upon the conserved biantennary N-glycans within the Fc domain provided the potent IVIg anti-inflammatory activity in autoimmune disease (2). Indeed, enrichment for the sialylated IgG (sIgG) fraction from IVIg pools increased the efficacy of treatment in mouse models of arthritis 100-fold in an IL-4-dependent fashion through receptors such as CD209 (DC-SIGN) (3, 4). Moreover, it was reported that sialylation of IgG also impacts antibody affinity maturation, although the mechanism underlying this phenomenon remains to be fully elucidated (5). These data indicate that sialylation serves as the mechanism underlying pleotropic IgG function (3,4,6).Epidemiologic analyses published since the reports cited above are consistent with this model. For example, female rheumatoid arthritis patients often go into remission during pregnancy and then relapse following childbirth. Analysis of sIgG levels before, during, and after pregnancy showed that the level of sIgG increases rapidly during pregnancy-induced remission, whereas during periods of exacerbated disease, sIgG is essentially undetectable (7,8). To date, it is unclear whether IgG sialylation patterns precede or result from the inflammatory state, and essentially nothing is known about the regulatory mecha...

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“…Subsequently, Fc-dependent mechanisms result in the formation of a proinflammatory milieu in the skin (31). Complement activation significantly (15,32,33), but not exclusively (34), contributes to the formation of this proinflammatory milieu. Finally, proteases, such as those released from skin-infiltrated inflammatory cells were seen in this study, and the induction of EBA led to increased endothelial ICAM-1 expression, which was absent if IL-1 function was blocked.…”

Section: Discussionmentioning

confidence: 99%

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Sadeghi

Lockmann

Hund

et al. 2015

The Journal of Immunology

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Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1β in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1α and IL-1β expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R–deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti–IL-1β. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R–deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1–stimulated, but not on TNF-α–stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11–deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti–IL-1β in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs.

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Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1

Cited by 404 publications

References 40 publications

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

B-cell–independent sialylation of IgG

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

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