Recapitulation of IVIG Anti-Inflammatory Activity with a Recombinant IgG Fc

Anthony, Robert M.; Nimmerjahn, Falk; Ashline, David J.; Reinhold, Vernon N.; Paulson, James C.; Ravetch, Jeffrey V.

doi:10.1126/science.1154315

Cited by 757 publications

(766 citation statements)

References 34 publications

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“…Interestingly, the linkage of sialic acid to the galactose residue was of great importance. Whereas both the 2,3-and 2,6-linked sialic acid residues resulted in a reduced affinity for cellular Fc␥ receptors, only the IgG molecules with 2,6-linked sialic acid had the capacity to suppress autoimmune diseases (12). Our results are consistent with those results, since we observed not only a hypogalactosylation, but also a 2,6-hyposialylation of the IgG molecules in patients with active GPA, but not in patients with remitted disease.…”

Section: Discussionsupporting

confidence: 92%

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Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Espy

Morelle²,

Kavian

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether the glycosylation and sialylation levels of anti-proteinase 3 (anti-PR3) antibodies could affect their pathogenicity, and whether these levels could be correlated with the activity of granulomatosis with polyangiitis (Wegener's) (GPA).Methods. Forty-two serum samples positive for anti-PR3 antibodies from 42 patients with active or weakly active/inactive GPA were included. Anti-PR3 antibodies were assayed by enzyme-linked immunosorbent assay, and their levels of glycosylation and sialylation were assessed by enzyme-linked lectin assay. The glycosylation and sialylation levels of IgG purified from the serum of healthy donors and patients with active, remitted, or weakly active disease were assessed by permethylation and mass spectrometry analysis of glycans, following neuraminidase digestion. The neutrophil oxidative burst induced by purified IgG was assayed by spectrofluorimetry.Results. The mean sialylation ratio of anti-PR3 antibodies was significantly lower in patients with active disease than in patients with weakly active or inactive disease, and this was inversely correlated with the Birmingham Vasculitis Activity Score (BVAS) (P < 0.0001). Similar results were obtained using the BVAS/ GPA. The area under the receiver operating characteristic curve for the sialylation ratio of anti-PR3 antibodies, as a test to determine the activity of GPA, was 0.82 (P ‫؍‬ 0.0006). The characterization of N-glycans showed a decrease in 2,6-linked sialylated N-glycans and an increase in dHex 1 Hex 3 HexNAc 4 (mass/charge 1,836) agalactosylated structures in purified IgG from patients with active disease compared with controls. The anti-PR3 antibody-induced oxidative burst of neutrophils was inversely correlated with the sialylation levels of anti-PR3 IgG.

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Section: Discussionsupporting

confidence: 92%

“…Two examples of this process can be presented. First, the level of sialylation of Fc␥ fragments was found to modulate the pathogenic effect of autoantibodies in a murine model of immune thrombocytopenia (12). Second, the level of sialylation of the IgG antibodies in intravenous immunoglobulin preparations can modulate their antiinflammatory effects.…”

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confidence: 99%

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Espy

Morelle²,

Kavian

et al. 2011

Arthritis & Rheumatism

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“…Recently, it has been determined that the sialylated IgG component of human IVIG binds to a lectin receptor dendritic cell-specific intracellular adhesion molecule 3-grabbing nonintegrin on dendritic cells, leading to the secretion of IL-33, which upregulates IL-4 secretion by basophils and leads to the increased expression of FcgRIIb on myeloid cells (22). Taken together with our results, these findings offer insights into the mechanism of action of IVIG for the treatment of human autoimmune disease, specifically the critical importance of FcgRIIb expression on myeloid cells in the protection from Ab-mediated injury (23).…”

Section: Discussionsupporting

confidence: 71%

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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“…The use of IVIg in the treatment of SLE can result in partial to complete remission in patients with various manifestations of SLE [reviewed in (ZandmanGoddard et al 2005)]; however, its use is often restricted to SLE patients who did not respond to standard treatment (Sherer and Shoenfeld 2006a). The antiinflammatory properties of IVIg have been invoked to explain its therapeutic effects in the treatment of autoimmune diseases, including SLE (Anthony et al 2008). Alternatively, a possible connection between the immunomodulatory mechanisms of IVIg and SLE treatment could involve blockade of BAFF through anti-BAFF (Le Pottier et al 2007;Toubi and Shoenfeld 2004a;Vani et al 2008) or neutralization of pathogenic anti-dsDNA through anti-idiotypic antibodies, as reported in mouse models (Shoenfeld et al 2002).…”

Section: Introductionmentioning

confidence: 99%

CD40-activated B cells from patients with systemic lupus erythematosus can be modulated by therapeutic immunoglobulins in vitro

Néron

Boire

Dussault

et al. 2009

Arch. Immunol. Ther. Exp.

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Introduction: Aberrant signaling within and between B and T cells, considered to be central in systemic lupus erythematosus (SLE), could depend on enhanced CD40-CD154 activation. As a result, autoreactive B cells, normally anergic, differentiate and secrete antibodies attacking several normal tissues. Thus restorating B cell homeostasis might help control this disease. In this study, two facets of SLE B cells were investigated, namely their in vitro response to CD40-CD154 and the effect of treatment with human immunoglobulins for intravenous use (IVIg). Materials and Methods: Blood samples from SLE patients and healthy volunteers were obtained and used to isolate B cells, which were activated through CD40 in the presence or absence of IVIg. The phenotype, proliferation, and differentiation of the SLE B cells were determined and compared with those of control B cells using flow cytometry and standard ELISA. Results: In this model, CD40-activated SLE B cells, as control B cells, proliferated and differentiated and were characterized by the emergence of CD19 lo CD38 ++ CD138 + CD27 ++ cells. IVIg treatment of the CD40-activated SLE B cells resulted in higher differentiation, characterized by increased secretion rates of IgG and IgM, as reported previously for control B cells. Conclusions: Taken as a whole, such accelerated differentiation of CD40-activated B cells suggests that IVIg may participate in re-equilibration of the antibody repertoire by replacing pathological antibodies by de novo harmless antibodies.

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Recapitulation of IVIG Anti-Inflammatory Activity with a Recombinant IgG Fc

Cited by 757 publications

References 34 publications

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

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

CD40-activated B cells from patients with systemic lupus erythematosus can be modulated by therapeutic immunoglobulins in vitro

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