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.
N1 - Funding Information:
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.
Funding Information:
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
Funding Information:
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.
Publisher Copyright:
© 2021 The Authors
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.
U2 - 10.1016/j.jid.2021.06.007
DO - 10.1016/j.jid.2021.06.007
M3 - 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 -