The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases

Sesărman, Alina; Vidarsson, Gestur; Sitaru, Cassian

doi:10.1007/s00018-010-0318-6

Cited by 47 publications

(38 citation statements)

References 207 publications

(161 reference statements)

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“…By a similar mechanism, hFcRn in endothelial cells may mediate transcytosis from the stroma into the fetal circulation main topic IgG-linked threats to the fetus and neonate: transport of autoimmune and alloimmune antibodies Auto-immune disorders affect 5-8% of the general population. In diseases such as systemic lupus erythematosus, tissue is damaged primarily by high affinity IgG autoantibodies [30]. The pathogenic potential of these autoantibodies directly correlates with their serum concentration, which in turn is regulated by hFcRn.…”

Section: Mechanism Of Transplacental Igg Transportmentioning

confidence: 99%

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HFcRn-mediated transplacental immunoglobulin G transport: Protection of and threat to the human fetus and newborn

Ellinger

Fuchs

2012

Wien Med Wochenschr

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In human newborns, endogenous levels of plasma immunoglobulin G (IgG) begin to rise slowly after birth following exposure to the environment. For immunoprotection during fetal and early neonatal life, maternal IgG is provided by transplacental transport. While cellular immunoprotective IgG effects are mainly triggered by FcγRI, -RII and -RIII, transplacental IgG transfer is mediated by the MHC class I-like neonatal Fc-receptor, hFcRn. This compact review explains the mechanism of hFcRn-mediated IgG transcytosis across the placental barrier - syncytiotrophoblast and fetal endothelial cells. Restrictions of this IgG transport are summarized. These include IgG subclass discrimination and limited IgG transport before the third trimester that can cause insufficient protection from infections of preterm (≤ 35 th week) delivered babies. As hFcRn does not discriminate beneficial from hazardous IgGs, maternal auto- and alloimmune as well as therapeutic antibodies can reach the fetus. The consequences including severe diseases of the newborn are summarized in this article.

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Section: Mechanism Of Transplacental Igg Transportmentioning

confidence: 99%

“…Existing autoimmune therapies most likely also modulate the hFcRn function. Systemic administration of corticosteroids might influence the expression level of hFcRn, while in high-dose IVIG-therapy, saturation of hFcRn is an important factor [30].…”

Section: Mechanism Of Transplacental Igg Transportmentioning

confidence: 99%

HFcRn-mediated transplacental immunoglobulin G transport: Protection of and threat to the human fetus and newborn

Ellinger

Fuchs

2012

Wien Med Wochenschr

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“…Although it is well established that FcRn ("neonatal" Fc receptor for IgG) contributes to IgG-mediated autoimmune diseases by extending the life span of autoantibodies (14,15), recent research has demonstrated a possibility of IgG internalization through interactions with FcRn (16 -20). FcRn is a heterodimer of a ␤2-microglobulin light chain and a major histocompatibility complex class I-like heavy chain.…”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 99%

Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris

Chen

Chernyavsky

Webber

et al. 2015

Journal of Biological Chemistry

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Background:Patients with pemphigus vulgaris develop antibodies to both cell adhesion molecules and intracellular proteins. Results: On the keratinocyte cell membrane, pemphigus autoantibodies form complexes with FcRn internalizing and trafficking them to mitochondria. Conclusion:The pathogenic role of antimitochondrial autoantibodies is complementary to that of anti-desmoglein autoantibodies, because both are required to disrupt the epidermal barrier. Significance: FcRn represents a common acceptor protein for internalization of autoantibodies to intracellular proteins.

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“…IgG3 has however a short half-life in vivo , making it potentially less effective for mAb therapies [16]. It was demonstrated that human IgG1 antibodies, which are the most abundant IgG isotype in humans, inhibit FcRn-mediated transport and rescue of human IgG3, subsequently leading to lysosomal degradation of IgG3 [12,17]. Due to the shorter half-life and earlier assumptions that the longer hinge region of IgG3 would lead to enhanced proteolytic degradation no IgG3 therapeutic antibodies are under development so far [18,19].…”

Section: Introductionmentioning

confidence: 99%

Human IgG3 with extended half-life does not improve Fc-gamma receptor-mediated cancer antibody therapies in mice

et al. 2017

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BackgroundCurrent anti-cancer therapeutic antibodies that are used in the clinic are predominantly humanized or fully human immunoglobulin G1 (IgG1). These antibodies bind with high affinity to the target antigen and are efficient in activating the immune system via IgG Fc receptors and/or complement. In addition to IgG1, three more isotypes are present in humans, of which IgG3 has been found to be superior compared to human IgG1 in inducing antibody dependent cell cytotoxicity (ADCC), phagocytosis or activation of complement in some models. Nonetheless, no therapeutic human IgG3 mAbs have been developed due to the short in vivo half-life of most known IgG3 allotypes. In this manuscript, we compared the efficacy of V-gene matched IgG1 and IgG3 anti-tumour mAb (TA99) in mice, using natural variants of human IgG3 with short- or long half-life, differing only at position 435 with an arginine or histidine, respectively.ResultsIn vitro human IgG1 and IgG3 did not show any differences in opsonisation ability of B16F10-gp75 mouse melanoma cells. IgG1, however, was superior in inducing phagocytosis of tumour cells by mouse macrophages. Similarly, in a mouse peritoneal metastasis model we did not detect an improved effect of IgG3 in preventing tumour outgrowth. Moreover, replacing the arginine at position 435 for a histidine in IgG3 to enhance half-life did not result in better suppression of tumour outgrowth compared to wild type IgG3 when injected prior to tumour cell injection.ConclusionIn conclusion, human IgG3 does not have improved therapeutic efficacy compared to human IgG1 in a mouse tumour model.

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The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases

Cited by 47 publications

References 207 publications

HFcRn-mediated transplacental immunoglobulin G transport: Protection of and threat to the human fetus and newborn

HFcRn-mediated transplacental immunoglobulin G transport: Protection of and threat to the human fetus and newborn

Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris

Human IgG3 with extended half-life does not improve Fc-gamma receptor-mediated cancer antibody therapies in mice

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