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Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies
- Source :
- Arthritis & rheumatology (Hoboken, N.J.), 71(2), 210-221. John Wiley and Sons Ltd, Arthritis and Rheumatology, 71(2), 210-221
- Publication Year :
- 2019
-
Abstract
- Objective: Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods: Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results: Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion: These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.
- Subjects :
- 0301 basic medicine
Male
Arthritis
Antigen-Antibody Complex
medicine.disease_cause
Crystallography, X-Ray
Cross-reactivity
Clinical onset
Anti-Citrullinated Protein Antibodies
Arthritis, Rheumatoid
Cohort Studies
Mice
0302 clinical medicine
Antigen-Antibody Complex/ultrastructure
Receptors
Immunology and Allergy
skin and connective tissue diseases
Crystallography
Receptors, Chimeric Antigen
biology
Anti–citrullinated protein antibody
Rheumatoid/immunology
3. Good health
Anti-Citrullinated Protein Antibodies/immunology
Rheumatoid arthritis
Female
Antibody
musculoskeletal diseases
Arthritis, Rheumatoid/immunology
Immunology
Cross Reactions
03 medical and health sciences
Immune system
Rheumatology
medicine
Animals
Humans
Rheumatology and Autoimmunity
030203 arthritis & rheumatology
Reumatologi och inflammation
business.industry
Chimeric Antigen
medicine.disease
030104 developmental biology
biology.protein
X-Ray
Cross Reactions/immunology
business
Subjects
Details
- Language :
- English
- ISSN :
- 23265191
- Database :
- OpenAIRE
- Journal :
- Arthritis & rheumatology (Hoboken, N.J.), 71(2), 210-221. John Wiley and Sons Ltd, Arthritis and Rheumatology, 71(2), 210-221
- Accession number :
- edsair.doi.dedup.....0aad1b0a35433102dad76f3a1d212e34