In Translation: FcRn across the Therapeutic Spectrum

Qi, Timothy; Cao, Yanguang

doi:10.3390/ijms22063048

Cited by 32 publications

(26 citation statements)

References 226 publications

(323 reference statements)

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“…antibody recycling). It has been shown that in some tissues such as intestine, FcRn is important for the transcytosis of IgG through the epithelia, whereas FcRn-mediated transcytosis through endothelial cells may be a prerequisite for autoantibodies to gain access to their target tissues (reviewed in [32,34]). Therefore, we propose that in tissues such as the epidermis, FcRn may function in "seeding immunity" by transporting the soluble, monomeric autoantibodies towards the autoantibody target cells, epidermal keratinocytes in pemphigus (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, FcRn appears to mediate the lysosomal degradation of autoantibody-antigen immune complexes (IC) in the target cells of the autoantibodies [31,32,33]. A recent review by Qi and Cao is recommended for a thorough summary of FcRn functions [34]. Although it has been shown that keratinocytes endogenously express FcRn [35], a potential direct role of FcRn in the pathogenesis of pemphigus and in the transport of autoantibodies in keratinocytes has so far not been addressed.…”

Section: Introductionmentioning

confidence: 99%

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Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?

Zakrzewicz¹,

Würth²,

Beckert³

et al. 2021

Preprint

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Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the neonatal Fc receptor, FcRn, results in reduced autoantibody recycling and shortens their half-life, providing a valid treatment option for PV. We have here analyzed the role of FcRn in human keratinocytes treated with novel, recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. We show that blocking IgG binding on FcRn by efgartigimod, a recombinant Fc fragment that is undergoing clinical studies for pemphigus, stabilizes the keratinocyte monolayer, whereas the loss of desmoglein-3 is not prevented by efgartigimod. Our data show for the first time that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. Our data also imply that in keratinocytes, FcRn may have functions different from its known function in IgG recycling. Therefore, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?

Zakrzewicz¹,

Würth²,

Beckert³

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…For the complexation study described in the simulation set 1, following a previous study ( 43 ), the pHs 7.0 and 4.6 were chosen, respectively, due to the need to understand the behavior of the system in physiologic pH level conditions and the acidic pH of the endosomal environment. This is a reasonable choice to keep the general features of the present study even though the precise value of the pH in human cells can be slightly different from these numbers ( 111 ). For all simulations from set 2, pH was varied from 0 to 14 with an increment of 0.1 units of pH to explore all possible pH conditions.…”

Section: Methodsmentioning

confidence: 99%

Up State of the SARS-COV-2 Spike Homotrimer Favors an Increased Virulence for New Variants

Giron

Laaksonen

Silva

2021

Front. Med. Technol.

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The COVID-19 pandemic has spread worldwide. However, as soon as the first vaccines—the only scientifically verified and efficient therapeutic option thus far—were released, mutations combined into variants of SARS-CoV-2 that are more transmissible and virulent emerged, raising doubts about their efficiency. This study aims to explain possible molecular mechanisms responsible for the increased transmissibility and the increased rate of hospitalizations related to the new variants. A combination of theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out to quantify the stability of several spike trimeric structures at different conformational states and the free energy of interactions between the receptor-binding domain (RBD) and angiotensin-converting enzyme II (ACE2) for the most worrying variants. Electrostatic epitopes were mapped using the PROCEEDpKa method. These analyses showed that the increased virulence is more likely to be due to the improved stability to the S trimer in the opened state, in which the virus can interact with the cellular receptor, ACE2, rather than due to alterations in the complexation RBD-ACE2, since the difference observed in the free energy values was small (although more attractive in general). Conversely, the South African/Beta variant (B.1.351), compared with the SARS-CoV-2 wild type (wt), is much more stable in the opened state with one or two RBDs in the up position than in the closed state with three RBDs in the down position favoring the infection. Such results contribute to understanding the natural history of disease and indicate possible strategies for developing new therapeutic molecules and adjusting the vaccine doses for higher B-cell antibody production.

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“…Linking insulin to the fragment crystallizable (Fc) region of immunoglobulin G (IgG) extends the insulin's half-life because the fusion protein benefits from the same recycling pathway that confers a relatively long half-life to endogenous IgG [55,56]. When IgG is taken up by cells through micropinocytosis, the Fc region binds to the membranebound neonatal Fc receptor (FcRn) in acidified endocytic vesicles.…”

Section: Once-weekly Formulations: Technological Principlesmentioning

confidence: 99%