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The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy

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The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy. / Seifert, Larissa; Hoxha, Elion; Eichhoff, Anna M; Zahner, Gunther; Dehde, Silke; Reinhard, Linda; Koch-Nolte, Friedrich; Stahl, Rolf A K; Tomas, Nicola M.

in: J AM SOC NEPHROL, Jahrgang 29, Nr. 5, 05.2018, S. 1536-1548.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Seifert, L, Hoxha, E, Eichhoff, AM, Zahner, G, Dehde, S, Reinhard, L, Koch-Nolte, F, Stahl, RAK & Tomas, NM 2018, 'The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy', J AM SOC NEPHROL, Jg. 29, Nr. 5, S. 1536-1548. https://doi.org/10.1681/ASN.2017070805

APA

Seifert, L., Hoxha, E., Eichhoff, A. M., Zahner, G., Dehde, S., Reinhard, L., Koch-Nolte, F., Stahl, R. A. K., & Tomas, N. M. (2018). The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy. J AM SOC NEPHROL, 29(5), 1536-1548. https://doi.org/10.1681/ASN.2017070805

Vancouver

Seifert L, Hoxha E, Eichhoff AM, Zahner G, Dehde S, Reinhard L et al. The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy. J AM SOC NEPHROL. 2018 Mai;29(5):1536-1548. https://doi.org/10.1681/ASN.2017070805

Bibtex

@article{3cf626b8026b4e5abc4b3e12dad7f1bd,
title = "The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy",
abstract = "Background Thrombospondin type 1 domain-containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown.Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice.Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48-192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A.Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.",
keywords = "Journal Article",
author = "Larissa Seifert and Elion Hoxha and Eichhoff, {Anna M} and Gunther Zahner and Silke Dehde and Linda Reinhard and Friedrich Koch-Nolte and Stahl, {Rolf A K} and Tomas, {Nicola M}",
note = "Copyright {\textcopyright} 2018 by the American Society of Nephrology.",
year = "2018",
month = may,
doi = "10.1681/ASN.2017070805",
language = "English",
volume = "29",
pages = "1536--1548",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "5",

}

RIS

TY - JOUR

T1 - The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy

AU - Seifert, Larissa

AU - Hoxha, Elion

AU - Eichhoff, Anna M

AU - Zahner, Gunther

AU - Dehde, Silke

AU - Reinhard, Linda

AU - Koch-Nolte, Friedrich

AU - Stahl, Rolf A K

AU - Tomas, Nicola M

N1 - Copyright © 2018 by the American Society of Nephrology.

PY - 2018/5

Y1 - 2018/5

N2 - Background Thrombospondin type 1 domain-containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown.Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice.Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48-192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A.Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.

AB - Background Thrombospondin type 1 domain-containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown.Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice.Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48-192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A.Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.

KW - Journal Article

U2 - 10.1681/ASN.2017070805

DO - 10.1681/ASN.2017070805

M3 - SCORING: Journal article

C2 - 29555830

VL - 29

SP - 1536

EP - 1548

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 5

ER -