Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition
Open Access
- 21 July 2021
- journal article
- research article
- Published by MDPI AG in Antibodies
- Vol. 10 (3), 27
- https://doi.org/10.3390/antib10030027
Abstract
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.Keywords
Funding Information
- Lundbeckfonden (R231-2016-3622)
This publication has 33 references indexed in Scilit:
- Cross‐reactivity of a human IgG1 anticitrullinated fibrinogen monoclonal antibody to a citrullinated profilaggrin peptideProtein Science, 2012
- Anti-cyclic citrullinated peptide antibodies are a collection of anti-citrullinated protein antibodies and contain overlapping and non-overlapping reactivitiesAnnals Of The Rheumatic Diseases, 2010
- Is the incidence of rheumatoid arthritis rising?: Results from Olmsted County, Minnesota, 1955–2007Arthritis & Rheumatism, 2010
- Anti–citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritisArthritis Care & Research, 2009
- Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolaseArthritis & Rheumatism, 2008
- Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 allelesAnnals Of The Rheumatic Diseases, 2008
- Gene-Gene and Gene-Environment Interactions Involving HLA-DRB1, PTPN22, and Smoking in Two Subsets of Rheumatoid ArthritisAmerican Journal of Human Genetics, 2007
- The Role of Citrullinated Proteins Suggests a Novel Mechanism in the Pathogenesis of Multiple SclerosisNeurochemical Research, 2006
- A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullinationArthritis & Rheumatism, 2005
- Protein Unfolding by Peptidylarginine DeiminaseOnline Journal of Public Health Informatics, 1996