Targeting the Fc receptor in autoimmune disease

Li, Xinrui; Kimberly, Robert P.

doi:10.1517/14728222.2014.877891

Cited by 56 publications

(48 citation statements)

References 173 publications

(135 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We speculate that these increases were related to immune complex‐mediated inflammation (e.g. HS–IgG immune complexes), as described previously in other models . Further experiments are needed to confirm this hypothesis.…”

Section: Discussionsupporting

confidence: 80%

Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses

Salerno-Gonçalves

Safavie

Fasano

et al. 2016

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummarySecretory immunoglobulin A (SIgA) antibodies play an important role in protecting the mucosal surfaces against pathogens and maintaining homeostasis with the commensal microbiota. Because a substantial portion of the gut microbiota is coated with SIgA, we hypothesized that microbiota–SIgA complexes are important for the maintenance of gut homeostasis. Here we investigated the relationship between microbiota–SIgA complexes and inflammatory epithelial cell responses. We used a multi‐cellular three‐dimensional (3D) organotypical model of the human intestinal mucosa composed of an intestinal epithelial cell line and primary human lymphocytes/monocytes, endothelial cells and fibroblasts. We also used human SIgA from human colostrum, and a prominent bacterial member of the first colonizers, Escherichia coli, as a surrogate commensal. We found that free and microbiota‐complexed SIgA triggered different epithelial responses. While free SIgA up‐regulated mucus production, expression of polymeric immunoglobulin receptor (pIgR) and secretion of interleukin‐8 and tumoir necrosis factor‐α, microbiota‐complexed SIgA mitigated these responses. These results suggest that free and complexed SIgA have different functions as immunoregulatory agents in the gut and that an imbalance between the two may affect gut homeostasis.

show abstract

Section: Discussionsupporting

confidence: 80%

Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses

Salerno-Gonçalves

Safavie

Fasano

et al. 2016

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…A considerable FcRn binding affinity at high pH, such as the ABDEG variant, 16 limits the amount of FcRn molecules available for subsequent recycling, 43 and leads to the rapid degradation of the circulating antibodies, which is a concept used for a promising treatment of autoimmune diseases. 44,45 Furthermore, SELDEGs can selectively degrade antigenspecific antibodies through lysosomal degradation without affecting other host antibodies. 46 Although not within the scope of this study, variants identified here could have desired or improved properties for application in other types of disease treatment beyond antibody half-life extension.…”

Section: Discussionmentioning

confidence: 99%

Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life

Mackness¹,

Jaworski²,

Boudanova³

et al. 2019

mAbs

View full text Add to dashboard Cite

The neonatal Fc receptor (FcRn) promotes antibody recycling through rescue from normal lysosomal degradation. The binding interaction is pH-dependent with high affinity at low pH, but not under physiological pH conditions. Here, we combined rational design and saturation mutagenesis to generate novel antibody variants with prolonged half-life and acceptable development profiles. First, a panel of saturation point mutations was created at 11 key FcRn-interacting sites on the Fc region of an antibody. Multiple variants with slower FcRn dissociation kinetics than the wildtype (WT) antibody at pH 6.0 were successfully identified. The mutations were further combined and characterized for pH-dependent FcRn binding properties, thermal stability and the FcγRIIIa and rheumatoid factor binding. The most promising variants, YD (M252Y/T256D), DQ (T256D/T307Q) and DW (T256D/T307W), exhibited significantly improved binding to FcRn at pH 6.0 and retained similar binding properties as WT at pH 7.4. The pharmacokinetics in human FcRn transgenic mice and cynomolgus monkeys demonstrated that these properties translated to significantly prolonged plasma elimination half-life compared to the WT control. The novel variants exhibited thermal stability and binding to FcγRIIIa in the range comparable to clinically validated YTE and LS variants, and showed no enhanced binding to rheumatoid factor compared to the WT control. These engineered Fc mutants are promising new variants that are widely applicable to therapeutic antibodies, to extend their circulation half-life with obvious benefits of increased efficacy, and reduced dose and administration frequency.

show abstract

“…Activating FcγRs on human (FcγRI/IIa/IIc/IIIa) and murine (FcγRI/III/IV) phagocytic cells contain ITAM motifs that recruit Syk and activate the PI3k pathway (12). Activation of FcγRs (FcγRI, III, and IV in mouse) is regulated by co-ligation with ITIM-containing inhibitory (FcγRIIB) receptors.…”

Section: Introductionmentioning

confidence: 99%

Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus

Kang

Rogers

Monteith

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that peripheral blood mononuclear cells from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 weeks of age, and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.

show abstract

Targeting the Fc receptor in autoimmune disease

Cited by 56 publications

References 173 publications

Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses

Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses

Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life

Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus

Contact Info

Product

Resources

About