Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition
Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1–2% of the world population. In addition to the first discovered serologic markers for RA, the rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPAs) are even more specific for the disease compared to RFs an...
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doaj-b0d8626de9cb4f43b5c94f8d77233ebf2021-09-25T23:37:49ZengMDPI AGAntibodies2073-44682021-07-0110272710.3390/antib10030027Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and CompositionIlaria Fanelli0Paolo Rovero1Paul Robert Hansen2Jette Frederiksen3Gunnar Houen4Nicole Hartwig Trier5Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of NeuroFarBa, University of Florence, 50019 Sesto Fiorentino, ItalyInterdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of NeuroFarBa, University of Florence, 50019 Sesto Fiorentino, ItalyDepartment of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, DenmarkDepartment of Neurology, Rigshospitalet Glostrup, 2600 Glostrup, DenmarkDepartment of Neurology, Rigshospitalet Glostrup, 2600 Glostrup, DenmarkDepartment of Neurology, Rigshospitalet Glostrup, 2600 Glostrup, DenmarkRheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1–2% of the world population. In addition to the first discovered serologic markers for RA, the rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPAs) are even more specific for the disease compared to RFs and are found in 70–80% of RA patient sera. RA etiopathogenesis still needs to be elucidated, as different factors are proposed to be involved, such as Epstein–Barr virus infection. Hence, understanding the interaction between ACPAs and their citrullinated peptide targets is relevant for a better knowledge of RA pathophysiology and for diagnostic purposes. In this study, a cohort of RA sera, healthy control sera and multiple sclerosis sera were screened for reactivity to a variety of citrullinated peptides originating from α-enolase, pro-filaggrin, proteoglycan and Epstein–Barr nuclear antigen-2 by enzyme-linked immunosorbent assay. ACPA reactivity to citrullinated α-enolase peptides was found to depend on peptide length and peptide conformation, favouring cyclic (disulfide bond) conformations for long peptides and linear peptides for truncated ones. Additional investigations about the optimal peptide conformation for ACPA detection, employing pro-filaggrin and EBNA-2 peptides, confirmed these findings, indicating a positive effect of cyclization of longer peptides of approximately 20 amino acids. Moreover, screening of the citrullinated peptides confirmed that ACPAs can be divided into two groups based on their reactivity. Approximately 90% of RA sera recognize several peptide targets, being defined as cross-reactive or overlapping reactivities, and whose reactivity to the citrullinated peptide is considered primarily to be backbone-dependent. In contrast, approximately 10% recognize a single target and are defined as nonoverlapping, primarily depending on the specific amino acid side-chains in the epitope for a stable interaction. Collectively, this study contributed to characterize epitope composition and structure for optimal ACPA reactivity and to obtain further knowledge about the cross-reactive nature of ACPAs.https://www.mdpi.com/2073-4468/10/3/27anti-citrullinated protein antibodiescitrullinated peptidesepitopesrheumatoid arthritis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ilaria Fanelli Paolo Rovero Paul Robert Hansen Jette Frederiksen Gunnar Houen Nicole Hartwig Trier |
spellingShingle |
Ilaria Fanelli Paolo Rovero Paul Robert Hansen Jette Frederiksen Gunnar Houen Nicole Hartwig Trier Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition Antibodies anti-citrullinated protein antibodies citrullinated peptides epitopes rheumatoid arthritis |
author_facet |
Ilaria Fanelli Paolo Rovero Paul Robert Hansen Jette Frederiksen Gunnar Houen Nicole Hartwig Trier |
author_sort |
Ilaria Fanelli |
title |
Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition |
title_short |
Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition |
title_full |
Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition |
title_fullStr |
Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition |
title_full_unstemmed |
Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition |
title_sort |
specificity of anti-citrullinated protein antibodies to citrullinated α-enolase peptides as a function of epitope structure and composition |
publisher |
MDPI AG |
series |
Antibodies |
issn |
2073-4468 |
publishDate |
2021-07-01 |
description |
Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1–2% of the world population. In addition to the first discovered serologic markers for RA, the rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPAs) are even more specific for the disease compared to RFs and are found in 70–80% of RA patient sera. RA etiopathogenesis still needs to be elucidated, as different factors are proposed to be involved, such as Epstein–Barr virus infection. Hence, understanding the interaction between ACPAs and their citrullinated peptide targets is relevant for a better knowledge of RA pathophysiology and for diagnostic purposes. In this study, a cohort of RA sera, healthy control sera and multiple sclerosis sera were screened for reactivity to a variety of citrullinated peptides originating from α-enolase, pro-filaggrin, proteoglycan and Epstein–Barr nuclear antigen-2 by enzyme-linked immunosorbent assay. ACPA reactivity to citrullinated α-enolase peptides was found to depend on peptide length and peptide conformation, favouring cyclic (disulfide bond) conformations for long peptides and linear peptides for truncated ones. Additional investigations about the optimal peptide conformation for ACPA detection, employing pro-filaggrin and EBNA-2 peptides, confirmed these findings, indicating a positive effect of cyclization of longer peptides of approximately 20 amino acids. Moreover, screening of the citrullinated peptides confirmed that ACPAs can be divided into two groups based on their reactivity. Approximately 90% of RA sera recognize several peptide targets, being defined as cross-reactive or overlapping reactivities, and whose reactivity to the citrullinated peptide is considered primarily to be backbone-dependent. In contrast, approximately 10% recognize a single target and are defined as nonoverlapping, primarily depending on the specific amino acid side-chains in the epitope for a stable interaction. Collectively, this study contributed to characterize epitope composition and structure for optimal ACPA reactivity and to obtain further knowledge about the cross-reactive nature of ACPAs. |
topic |
anti-citrullinated protein antibodies citrullinated peptides epitopes rheumatoid arthritis |
url |
https://www.mdpi.com/2073-4468/10/3/27 |
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