Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis

Malgorzata Trela, Shantha Perera, Thomas Sheeran, Paul Rylance, Paul N. Nelson, Kesley Attridge

Research output: Contribution to journalArticle

Abstract

Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the two most prevalent autoantibodies in rheumatoid arthritis (RA), and are thought to have distinct autoantigen targets. Whilst RF targets the Fc region of antibodies, ACPAs target a far broader spectrum of citrullinated peptides. Here we demonstrate significant sequence and structural homology between proposed RF target epitopes in IgG1 Fc and the ACPA target fibrinogen. Two of the three homologous sequences were susceptible to citrullination, and this modification, which occurs extensively in RA, permitted significant cross-reactivity of RF+ patient sera with fibrinogen in both western blots and ELISAs. Crucially, this reactivity was specific to RF as it was absent in RF− patient and healthy control sera, and could be inhibited by pre-incubation with IgG1 Fc. These studies establish fibrinogen as a common target for both RF and ACPAs, and suggest a new mechanism in RF-mediated autoimmune diseases wherein RF may act as a precursor from which the ACPA response evolves.
Original languageEnglish
Article number12068
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 19 Aug 2019

Fingerprint

Rheumatoid Factor
Epitopes
Rheumatoid Arthritis
Fibrinogen
Antibodies
Sequence Homology
Proteins
Immunoglobulin G
Autoantigens
Serum
Autoantibodies
Autoimmune Diseases
Antibody Formation
Anti-Idiotypic Antibodies
Western Blotting
Enzyme-Linked Immunosorbent Assay
Peptides

Bibliographical note

Open Access - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Funding: South Staffordshire Medical Foundation Rotha Abraham Bequest, the Royal Wolverhampton Hospital Charity, the New Cross Kidney Patients Association, and The James Beattie Charitable Trust.

Cite this

Trela, Malgorzata ; Perera, Shantha ; Sheeran, Thomas ; Rylance, Paul ; Nelson, Paul N. ; Attridge, Kesley. / Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
@article{5d00b79845ed494c859ec6f84ec0542f,
title = "Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis",
abstract = "Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the two most prevalent autoantibodies in rheumatoid arthritis (RA), and are thought to have distinct autoantigen targets. Whilst RF targets the Fc region of antibodies, ACPAs target a far broader spectrum of citrullinated peptides. Here we demonstrate significant sequence and structural homology between proposed RF target epitopes in IgG1 Fc and the ACPA target fibrinogen. Two of the three homologous sequences were susceptible to citrullination, and this modification, which occurs extensively in RA, permitted significant cross-reactivity of RF+ patient sera with fibrinogen in both western blots and ELISAs. Crucially, this reactivity was specific to RF as it was absent in RF− patient and healthy control sera, and could be inhibited by pre-incubation with IgG1 Fc. These studies establish fibrinogen as a common target for both RF and ACPAs, and suggest a new mechanism in RF-mediated autoimmune diseases wherein RF may act as a precursor from which the ACPA response evolves.",
author = "Malgorzata Trela and Shantha Perera and Thomas Sheeran and Paul Rylance and Nelson, {Paul N.} and Kesley Attridge",
note = "Open Access - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Funding: South Staffordshire Medical Foundation Rotha Abraham Bequest, the Royal Wolverhampton Hospital Charity, the New Cross Kidney Patients Association, and The James Beattie Charitable Trust.",
year = "2019",
month = "8",
day = "19",
doi = "10.1038/s41598-019-48176-3",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis. / Trela, Malgorzata; Perera, Shantha; Sheeran, Thomas; Rylance, Paul; Nelson, Paul N.; Attridge, Kesley.

In: Scientific Reports, Vol. 9, No. 1, 12068, 19.08.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis

AU - Trela, Malgorzata

AU - Perera, Shantha

AU - Sheeran, Thomas

AU - Rylance, Paul

AU - Nelson, Paul N.

AU - Attridge, Kesley

N1 - Open Access - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Funding: South Staffordshire Medical Foundation Rotha Abraham Bequest, the Royal Wolverhampton Hospital Charity, the New Cross Kidney Patients Association, and The James Beattie Charitable Trust.

PY - 2019/8/19

Y1 - 2019/8/19

N2 - Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the two most prevalent autoantibodies in rheumatoid arthritis (RA), and are thought to have distinct autoantigen targets. Whilst RF targets the Fc region of antibodies, ACPAs target a far broader spectrum of citrullinated peptides. Here we demonstrate significant sequence and structural homology between proposed RF target epitopes in IgG1 Fc and the ACPA target fibrinogen. Two of the three homologous sequences were susceptible to citrullination, and this modification, which occurs extensively in RA, permitted significant cross-reactivity of RF+ patient sera with fibrinogen in both western blots and ELISAs. Crucially, this reactivity was specific to RF as it was absent in RF− patient and healthy control sera, and could be inhibited by pre-incubation with IgG1 Fc. These studies establish fibrinogen as a common target for both RF and ACPAs, and suggest a new mechanism in RF-mediated autoimmune diseases wherein RF may act as a precursor from which the ACPA response evolves.

AB - Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the two most prevalent autoantibodies in rheumatoid arthritis (RA), and are thought to have distinct autoantigen targets. Whilst RF targets the Fc region of antibodies, ACPAs target a far broader spectrum of citrullinated peptides. Here we demonstrate significant sequence and structural homology between proposed RF target epitopes in IgG1 Fc and the ACPA target fibrinogen. Two of the three homologous sequences were susceptible to citrullination, and this modification, which occurs extensively in RA, permitted significant cross-reactivity of RF+ patient sera with fibrinogen in both western blots and ELISAs. Crucially, this reactivity was specific to RF as it was absent in RF− patient and healthy control sera, and could be inhibited by pre-incubation with IgG1 Fc. These studies establish fibrinogen as a common target for both RF and ACPAs, and suggest a new mechanism in RF-mediated autoimmune diseases wherein RF may act as a precursor from which the ACPA response evolves.

UR - http://www.nature.com/articles/s41598-019-48176-3

UR - http://www.scopus.com/inward/record.url?scp=85071048495&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-48176-3

DO - 10.1038/s41598-019-48176-3

M3 - Article

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 12068

ER -