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^*

^*Corresponding author for this work

7 Citations (Scopus)

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
Journal	Journal of Investigative Dermatology
Volume	141
Issue number	12
Pages (from-to)	2820-2828
Number of pages	9
ISSN	0022-202X
DOIs	https://doi.org/10.1016/j.jid.2021.06.007
Publication status	Published - 12.2021

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 CMH is a consultant to Argenx and viDA Therapeutics. CMH has a provisional patent for using BP mAbs to deliver biologic agents to the basement membrane zone. CP and LK are employees of the EUROIMMUN AG, a company that develops, produces, and manufactures immunoassays for the detection of disease-associated antibodies. DZ declares consultants honoraria from UCB, Almirall, and Argenx; grants from Biotest, EUROIMMUN, and Fresenius; and speakers’ honoraria/travel support from Biotest, Fresenius, Miltenyi, Roche, Biogen, AbbVie, UCB, Janssen, and Novartis. The remaining authors state no conflict of interest.

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

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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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{4e2cffb301a2446ea11ec66ffc2c3e6c,

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 = "English",

volume = "141",

pages = "2820--2828",

journal = "Journal of Investigative Dermatology",

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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 - Journal articles

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

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