Type I and type II Fc receptors regulate innate and adaptive immunity

Pincetic, Andrew; Bournazos, Stylianos; DiLillo, David J.; Maamary, Jad; Wang, Taia T.; Dahan, Rony; Fiebiger, Benjamin-Maximillian; Ravetch, Jeffrey V.

doi:10.1038/ni.2939

Cited by 416 publications

(449 citation statements)

References 104 publications

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“…This switch in receptor specificity coincides with a switch in effector function in vivo, as sialylated IgG suppresses inflammation in mouse models of autoimmunity. Recent structural data support an earlier computational model that sialylation increases the conformational flexibility of the C H 2 domain, sampling conformations compatible with type II FcR binding (8,20,36).…”

Section: Discussionsupporting

confidence: 63%

“…A complex, N-linked glycan attached to the C H 2 domain of IgG Fc regulates the interaction with these classes of FcRs by modulating the structure of the Fc to alternate between type I and type II binding conformations (8,11,20). The presence of an α2,6-linked sialic acid in this Fc-associated glycan results in reduced affinity for type I FcRs and enhanced binding to type II FcRs, such as DC-SIGN and CD23 (8,11,15). This switch in receptor specificity coincides with a switch in effector function in vivo, as sialylated IgG suppresses inflammation in mouse models of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

“…Its antiinflammatory activity has been shown to result from the presence of a specific glycan, the α2,6-sialylated, complex biantennary structure present on the C H 2 domain of the fragment crystallizable domain (Fc) and found in a small proportion of heterogeneous antibody preparations in IVIG (4). Sialylation of the Fc glycan on the C H 2 domain results in IgGs that can engage type II Fc receptors (FcRs) such as specific ICAM-3 grabbing non-integrin-related 1 (SIGN-R1), dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), and CD23 (5)(6)(7)(8), while reducing their binding affinity to type I FcRs (9)(10)(11). Studies in mouse models of serum-induced arthritis, antibody-dependent ITP, nephrotoxic nephritis, and autoimmune blistering diseases confirmed the antiinflammatory activity of the sialylated Fc, whether from IVIG or generated from recombinantly expressed IgG1 (5,9,12,13).…”

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confidence: 99%

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Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs

Fiebiger

Maamary

Pincetic

et al. 2015

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

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The antiinflammatory activity of intravenous immunoglobulin (IVIG) is dependent on the presence of sialic acid in the core IgG fragment crystallizable domain (Fc) glycan, resulting in increased conformational flexibility of the C H 2 domain with corresponding modulation of Fc receptor (FcR) binding specificity from type I to type II receptors. Sialylated IgG Fc (sFc) increases the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory receptor FcγRIIB. We have found that the structural alterations induced by sialylation can be mimicked by specific amino acid modifications to the C H 2 domain. An IgG Fc variant with a point mutation at position 241 (F→A) exhibits antiinflammatory activity even in the absence of sialylation. F241A and sFc protect mice from arthritis in the K/BxN-induced model and, in the T cell-mediated experimental autoimmune encephalomyelitis (EAE) mouse model, suppress disease by specifically activating regulatory T cells (T reg cells). Protection by these antiinflammatory Fcs in both antibody-and T cell-mediated autoimmune diseases required type II FcRs and the induction of IL-33. These results further clarify the mechanism of action of IVIG in both antibody-and T cellmediated inflammatory diseases and demonstrate that Fc variants that mimic the structural alterations induced by sialylation, such as F241A, can be promising therapeutic candidates for the treatment of various autoimmune disorders.IgG Fc sialylation | conformational change | antiinflammatory | T reg cells

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs

Fiebiger

Maamary

Pincetic

et al. 2015

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

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“…with specific antigens and a fragment crystallizable domain (Fc fragment) that interacts with cellular receptors (Fc receptors) known to play critical functions in modulating the activation state of immune cells (11). The IgG Fc fragment contains a conserved N-linked glycan at position N297.…”

Section: Significancementioning

confidence: 99%

“…For example, removal of fucose from the IgG N-glycan core has been shown to increase its affinity for Fc gamma receptor IIIa (FcγRIIIa), leading to enhanced antibody-dependent cellular cytotoxicity (14). Sialylation, the addition of terminal sialic acid to N297 glycan, has also been shown to decrease the affinity for type I Fc receptors and increase the affinity for type II Fc receptors (11).…”

Section: Significancementioning

confidence: 99%

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Washburn

Schwab

Ortiz

et al. 2015

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

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Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.IVIg | sialylation | antibody | inflammation | autoimmune disease

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B Lymphocytes: Receptors

DeFranco

2015

Encyclopedia of Life Sciences

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B lymphocytes can synthesise Ig heavy chains that are either secreted or membrane‐bound, the latter having a transmembrane domain and a short cytoplasmic domain. Membrane‐bound Ig heavy chains and Ig light chains assemble in the ER with each other and with a heterodimer of Igα and Igβ, which mediate signalling and internalisation functions. The complex of these four polypeptides is called the B cell antigen receptor (BCR). BCR signalling occurs via three types of tyrosine kinases. Src‐family kinases phosphorylate the two tyrosine‐containing motif in the cytoplasmic domains of Igα and Igβ (the ITAMs), which recruits a second type of tyrosine kinase Syk. Syk is responsible for most downstream signalling, although calcium and diacylglycerol also require a third tyrosine kinase Btk. BCR signalling pathways are central to virtually all aspects of B cell biology, as they are required for B cell development, tolerance induction, survival and activation. Key Concepts Naïve B cells express their immunoglobulin as a cell surface receptor for antigen, called the BCR (B cell receptor for antigen). In developing precursors of B cells, the successful generation of an immunoglobulin heavy chain is sensed by the incorporation of that heavy chain into pre‐BCR molecules, which exhibit constitutive signalling. Signalling by the BCR controls development, survival and activation of B cells in a manner that is dependent on the developmental stage or activation state of the B cell. This signalling is important both for tolerisation of self‐reactive B cells and for activation of B cells recognising foreign antigen. Co‐receptors that recognise complement components, sialic acid residues, or IgG bound to antigens strongly enhance or inhibit signalling by the BCR to aid in self‐non‐self‐discrimination. The BCR is also an endocytic receptor that delivers antigen to internal compartments where protein antigens are processed into peptides and loaded onto MHC class II molecules to facilitate interactions with T cells, which are essential for production of high‐affinity antibodies. Defects in generation of BCRs or signalling components of the BCR result in B cell immunodeficiencies, the most common of which is due to loss‐of‐function mutations of the intracellular protein tyrosine kinase Btk, referred to as X‐linked agammaglobulinemia. B cell malignancies often have activated BCR signalling as a driver of their proliferation and/or survival, and selective Btk inhibitors are now approved therapeutics for some types of B cell malignancies.

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Type I and type II Fc receptors regulate innate and adaptive immunity

Cited by 416 publications

References 104 publications

Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs

Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

B Lymphocytes: Receptors

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