Citrullination only infrequently impacts peptide binding to HLA class II MHC

It has been hypothesized that HLA class II alleles associated with rheumatoid arthritis (RA) preferentially present self-antigens altered by post-translational modification, such as citrullination. To understand the role of citrullination we tested four RA-associated citrullinated epitopes and their...

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Bibliographic Details
Published in:PloS one 2017-05, Vol.12 (5), p.e0177140
Main Authors: Sidney, John, Becart, Stephane, Zhou, Mimi, Duffy, Karen, Lindvall, Mikaela, Moore, Erin C, Moore, Eugene L, Rao, Tadimeti, Rao, Navin, Nielsen, Morten, Peters, Bjoern, Sette, Alessandro
Format: Article
Language:English
Subjects:
Affinity
Aggrecan
Alleles
Amino acid sequence
Antibodies
Antigens
Arginine
Arthritis
Assaying
Autoantigens
Binding
Biology and Life Sciences
CD4 antigen
Cell activation
Citrulline
Citrulline - metabolism
Clonal selection
Coding
Collagen
Collagen (type II)
Conserved sequence
Correlation
Cytokines
Data bases
Destruction
Diagnosis
Drb1 protein
Enzymes
Epitopes
Epitopes - metabolism
Histocompatibility Antigens Class II - metabolism
Humans
Hypersensitivity
Immunology
Immunotherapy
Infections
Inflammation
Interception
Ligands
Lymphocytes
Lymphocytes B
Lymphocytes T
Medicine and Health Sciences
Mice
Nucleic acids
Pathogenesis
Pathogens
Patients
Peptides
Peptides - metabolism
Protein Binding
Proteins
R&D
Research & development
Research and Analysis Methods
Rheumatoid arthritis
Rheumatology
Risk factors
Structural analysis
Viruses
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Summary:It has been hypothesized that HLA class II alleles associated with rheumatoid arthritis (RA) preferentially present self-antigens altered by post-translational modification, such as citrullination. To understand the role of citrullination we tested four RA-associated citrullinated epitopes and their corresponding wild-type version for binding to 28 common HLA class II. Binding patterns were variable, and no consistent impact of citrullination was identified. Indeed, in one case citrullination significantly increased binding compared to the WT peptide, in another citrullination was associated with a reduction in promiscuity by 40%. For a more comprehensive analysis, we tested over 200 citrullinated peptides derived from vimentin and collagen II for their capacity to bind the RA-associated shared epitope alleles DRB1*01:01 and DRB1*04:01. The overall effect of citrullination on binding was found to be relatively minor, and only rarely associated with 3-fold increases or decreases in affinity. Previous studies have suggested that citrullination of MHC anchor residues, in particular P4, is associated with generation of novel RA-associated epitopes. However, analysis of the predicted MHC-binding cores of all peptides tested found that in modified peptides with increased binding affinity the citrullinated residue was predicted to occupy an anchor position in only a minority of cases. Finally, we also show that identification of citrullinated peptide binders could be facilitated by using the NetMHCIIpan 3.1 algorithm, representing citrullination as a wildcard. Our studies identify a total of 117 citrullinated peptides that bound RA-associated alleles with an affinity of 1000 nM or better.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0177140