Remote activation of a latent epitope in an autoantigen decoded with simulated b-factors

Yuan Ping Pang; Marta Casal Moura; Gwen E. Thompson; Darlene R. Nelson; Amber M. Hummel; Dieter E. Jenne; Daniel Emerling; Wayne Volkmuth; William H. Robinson; Ulrich Specks

doi:10.3389/fimmu.2019.02467

Remote activation of a latent epitope in an autoantigen decoded with simulated b-factors

Yuan Ping Pang, Marta Casal Moura, Gwen E. Thompson, Darlene R. Nelson, Amber M. Hummel, Dieter E. Jenne, Daniel Emerling, Wayne Volkmuth, William H. Robinson, Ulrich Specks

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

2 Scopus citations

Abstract

Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val¹⁰³ possessing a Ser195Ala mutation relative to wild-type PR3-Val¹⁰³ —offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val¹⁰³, a triple mutant of iPR3-Val¹⁰³, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val¹⁰³ was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val¹⁰³ was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3·ANCA interactions as new GPA treatments.

Original language	English (US)
Article number	2467
Journal	Frontiers in immunology
Volume	10
Issue number	OCT
DOIs	https://doi.org/10.3389/fimmu.2019.02467
State	Published - 2019

Keywords

Antigenicity
Antineutrophil cytoplasmic antibody
Autoantigen
Autoimmunity
B-factor
Proteinase 3

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.3389/fimmu.2019.02467

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title = "Remote activation of a latent epitope in an autoantigen decoded with simulated b-factors",

abstract = "Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103 —offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3·ANCA interactions as new GPA treatments.",

keywords = "Antigenicity, Antineutrophil cytoplasmic antibody, Autoantigen, Autoimmunity, B-factor, Proteinase 3",

author = "Pang, {Yuan Ping} and Moura, {Marta Casal} and Thompson, {Gwen E.} and Nelson, {Darlene R.} and Hummel, {Amber M.} and Jenne, {Dieter E.} and Daniel Emerling and Wayne Volkmuth and Robinson, {William H.} and Ulrich Specks",

note = "Publisher Copyright: {\textcopyright} 2019 Pang, Casal Moura, Thompson, Nelson, Hummel, Jenne, Emerling, Volkmuth, Robinson and Specks.",

year = "2019",

doi = "10.3389/fimmu.2019.02467",

language = "English (US)",

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AU - Pang, Yuan Ping

AU - Moura, Marta Casal

AU - Thompson, Gwen E.

AU - Nelson, Darlene R.

AU - Hummel, Amber M.

AU - Jenne, Dieter E.

AU - Emerling, Daniel

AU - Volkmuth, Wayne

AU - Robinson, William H.

AU - Specks, Ulrich

PY - 2019

Y1 - 2019

N2 - Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103 —offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3·ANCA interactions as new GPA treatments.

AB - Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103 —offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3·ANCA interactions as new GPA treatments.

KW - Antigenicity

KW - Antineutrophil cytoplasmic antibody

KW - Autoantigen

KW - Autoimmunity

KW - B-factor

KW - Proteinase 3

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Remote activation of a latent epitope in an autoantigen decoded with simulated b-factors

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Keywords

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