Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus

Shirin Emtenani; Saeedeh Ghorbanalipoor; Sarah Mayer-Hain; Khalaf Kridin; Lars Komorowski; Christian Probst; Takashi Hashimoto; Hendri H. Pas; Kaja Męcińska-Jundziłł; Rafał Czajkowski; Andreas Recke; Cord Sunderkötter; Stefan W. Schneider; Jennifer E. Hundt; Detlef Zillikens; Enno Schmidt; Ralf J. Ludwig; Christoph M. Hammers

doi:10.1016/j.jid.2021.06.007

Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus

Shirin Emtenani, Saeedeh Ghorbanalipoor, Sarah Mayer-Hain, Khalaf Kridin, Lars Komorowski, Christian Probst, Takashi Hashimoto, Hendri H. Pas, Kaja Męcińska-Jundziłł, Rafał Czajkowski, Andreas Recke, Cord Sunderkötter, Stefan W. Schneider, Jennifer E. Hundt, Detlef Zillikens, Enno Schmidt, Ralf J. Ludwig, Christoph M. Hammers

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies; however, models for the disease and more detailed pathophysiologic data are lacking. In this study, we aimed to establish in vitro models of disease for IgA pemphigus, allowing us to study the effects of the interaction of anti-keratinocyte IgA with cell surface FcαRs. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, in this study, we present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti–desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on FcαR-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of FcαR:IgA-Fc interaction, as confirmed in an additional model for IgA-dependent disease, that is, IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro and that IgA pemphigus and IgA vasculitis are FcαR-dependent disease entities that can be specifically targeted in these experimental systems.

Original language	English
Pages (from-to)	2820-2828
Number of pages	9
Journal	Journal of Investigative Dermatology
Volume	141
Issue number	12
DOIs	https://doi.org/10.1016/j.jid.2021.06.007
State	Published - Dec 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Funding

This work was funded by Deutsche Forschungsgemeinschaft structural grants CRU303 and EXC2167. Additional support came from RTG1727 and CSSL (both Deutsche Forschungsgemeinschaft) and from the Section of Medicine at the University of Luebeck, Luebeck, Germany (CS06-2019). We thank John R. Stanley of the Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania for reviewing the manuscript. This work was funded by Deutsche Forschungsgemeinschaft structural grants CRU303 and EXC2167. Additional support came from RTG1727 and CSSL (both Deutsche Forschungsgemeinschaft) and from the Section of Medicine at the University of Luebeck, Luebeck, Germany (CS06-2019). We thank John R. Stanley of the Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania for reviewing the manuscript. Conceptualization: CMH; Formal Analysis: CMH, SE, SG, SMH, AR; Investigation: SE, SG, SMH, LK, CP, CMH; Resources: SMH, LK, CP, TH, HHP, KMJ, RC, CS, JEH, CMH; Supervision: CMH, RJL; Writing - Original Draft Preparation: CMH, SE; Writing - Review and Editing: CMH, SE, SG, SMH, KK, TH, AR, CS, SWS, JEH, DZ, ES, RJL

Funders	Funder number
CSSL
University of Luebeck	CS06-2019
Deutsche Forschungsgemeinschaft	EXC2167, CRU303

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jid.2021.06.007

Cite this

Emtenani, S., Ghorbanalipoor, S., Mayer-Hain, S., Kridin, K., Komorowski, L., Probst, C., Hashimoto, T., Pas, H. H., Męcińska-Jundziłł, K., Czajkowski, R., Recke, A., Sunderkötter, C., Schneider, S. W., Hundt, J. E., Zillikens, D., Schmidt, E., Ludwig, R. J., & Hammers, C. M. (2021). Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus. Journal of Investigative Dermatology, 141(12), 2820-2828. https://doi.org/10.1016/j.jid.2021.06.007

@article{4e5a1cd9d553455d94f70eed2ee19222,

title = "Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus",

abstract = "Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies; however, models for the disease and more detailed pathophysiologic data are lacking. In this study, we aimed to establish in vitro models of disease for IgA pemphigus, allowing us to study the effects of the interaction of anti-keratinocyte IgA with cell surface FcαRs. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, in this study, we present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti–desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on FcαR-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of FcαR:IgA-Fc interaction, as confirmed in an additional model for IgA-dependent disease, that is, IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro and that IgA pemphigus and IgA vasculitis are FcαR-dependent disease entities that can be specifically targeted in these experimental systems.",

author = "Shirin Emtenani and Saeedeh Ghorbanalipoor and Sarah Mayer-Hain and Khalaf Kridin and Lars Komorowski and Christian Probst and Takashi Hashimoto and Pas, \{Hendri H.\} and Kaja M{\c e}ci{\'n}ska-Jundzi{\l}{\l} and Rafa{\l} Czajkowski and Andreas Recke and Cord Sunderk{\"o}tter and Schneider, \{Stefan W.\} and Hundt, \{Jennifer E.\} and Detlef Zillikens and Enno Schmidt and Ludwig, \{Ralf J.\} and Hammers, \{Christoph M.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

doi = "10.1016/j.jid.2021.06.007",

language = "אנגלית",

volume = "141",

pages = "2820--2828",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

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number = "12",

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Emtenani, S, Ghorbanalipoor, S, Mayer-Hain, S, Kridin, K, Komorowski, L, Probst, C, Hashimoto, T, Pas, HH, Męcińska-Jundziłł, K, Czajkowski, R, Recke, A, Sunderkötter, C, Schneider, SW, Hundt, JE, Zillikens, D, Schmidt, E, Ludwig, RJ & Hammers, CM 2021, 'Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus', Journal of Investigative Dermatology, vol. 141, no. 12, pp. 2820-2828. https://doi.org/10.1016/j.jid.2021.06.007

TY - JOUR

T1 - Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus

AU - Emtenani, Shirin

AU - Ghorbanalipoor, Saeedeh

AU - Mayer-Hain, Sarah

AU - Kridin, Khalaf

AU - Komorowski, Lars

AU - Probst, Christian

AU - Hashimoto, Takashi

AU - Pas, Hendri H.

AU - Męcińska-Jundziłł, Kaja

AU - Czajkowski, Rafał

AU - Recke, Andreas

AU - Sunderkötter, Cord

AU - Schneider, Stefan W.

AU - Hundt, Jennifer E.

AU - Zillikens, Detlef

AU - Schmidt, Enno

AU - Ludwig, Ralf J.

AU - Hammers, Christoph M.

PY - 2021/12

Y1 - 2021/12

N2 - Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies; however, models for the disease and more detailed pathophysiologic data are lacking. In this study, we aimed to establish in vitro models of disease for IgA pemphigus, allowing us to study the effects of the interaction of anti-keratinocyte IgA with cell surface FcαRs. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, in this study, we present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti–desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on FcαR-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of FcαR:IgA-Fc interaction, as confirmed in an additional model for IgA-dependent disease, that is, IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro and that IgA pemphigus and IgA vasculitis are FcαR-dependent disease entities that can be specifically targeted in these experimental systems.

AB - Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies; however, models for the disease and more detailed pathophysiologic data are lacking. In this study, we aimed to establish in vitro models of disease for IgA pemphigus, allowing us to study the effects of the interaction of anti-keratinocyte IgA with cell surface FcαRs. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, in this study, we present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti–desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on FcαR-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of FcαR:IgA-Fc interaction, as confirmed in an additional model for IgA-dependent disease, that is, IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro and that IgA pemphigus and IgA vasculitis are FcαR-dependent disease entities that can be specifically targeted in these experimental systems.

UR - https://www.scopus.com/pages/publications/85111942051

U2 - 10.1016/j.jid.2021.06.007

DO - 10.1016/j.jid.2021.06.007

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34246620

AN - SCOPUS:85111942051

SN - 0022-202X

VL - 141

SP - 2820

EP - 2828

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 12

ER -

Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus

Abstract

Bibliographical note

Funding

UN SDGs

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