Remote Activation of a Latent Epitope in an Autoantigen Decoded With Simulated B-Factors

被引：5

作者：

Pang, Yuan-Ping ^{[1
]}

Moura, Marta Casal ^{[2
]}

Thompson, Gwen E. ^{[2
]}

Nelson, Darlene R. ^{[2
]}

Hummel, Amber M. ^{[2
]}

Jenne, Dieter E. ^{[3
,4
]}

Emerling, Daniel ^{[5
]}

Volkmuth, Wayne ^{[5
]}

Robinson, William H. ^{[6
]}

Specks, Ulrich ^{[2
]}

机构：

[1] Mayo Clin, Comp Aided Mol Design Lab, Rochester, MN 55905 USA

[2] Mayo Clin, Thorac Dis Res Unit, Rochester, MN 55905 USA

[3] Helmholtz Zentrum Munchen, Comprehens Pneumol Ctr, Martinsried, Germany

[4] Max Planck Inst Neuroimmunol, Martinsried, Germany

[5] Atreca Inc, Redwood City, CA USA

[6] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA

来源：

FRONTIERS IN IMMUNOLOGY | 2019年 / 10卷

基金：

欧盟地平线“2020”;

关键词：

autoimmunity; autoantigen; antigenicity; antineutrophil cytoplasmic antibody; Proteinase; 3; B-factor; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; PROTEINASE-3; PR3; WEGENERS-GRANULOMATOSIS; NEUTROPHIL ELASTASE; MOLECULAR-DYNAMICS; CAPTURE-ELISA; RECOGNITION; REFINEMENT; INTERFERENCE; RESTRAINTS;

D O I：

10.3389/fimmu.2019.02467

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Mutants of a catalytically inactive variant of Proteinase 3 (PR3)-iPR3-Val(103) possessing a Ser195Ala mutation relative to wild-type PR3-Val(103)-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-Val(103), a triple mutant of iPR3-Val(103), bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val(103) was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val(103) 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 center dot ANCA interactions as new GPA treatments.

引用

页数：9

共 2 条

[1] MEDI 256-Activation and inhibition of latent serine proteases, complement factors B and C2
Fairlie, David P.
Le, Giang T.
Halili, Maria
Ruiz-Gomez, Gloria
Abbenante, John
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2008, 236
[2] Interaction of tumor necrosis factor receptor-associated factors with the latent membrane protein 1 is essential for activation of NF-κB
Wang, CX
Li, XY
Gu, HH
Deng, XY
Cao, Y
PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS, 2001, 28 (02) : 240 - 245

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