A Novel HLA–DRB1*10:01–Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis

Chemin, Karine; Pollastro, Sabrina; James, Eddie A.; Ge, Changrong; Albrecht, Inka; Herrath, Jessica; Gerstner, Christina; Tandre, Karolina; Rizzi, Thais S.; Rönnblom, Lars; Catrina, Anca I.; Holmdahl, Rikard; Klareskog, Lars; Vries, Niek de; Malmström, Vivianne

doi:10.1002/art.39553

Cited by 40 publications

(30 citation statements)

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“…Indeed, an example of a peptide that appears negative in MHC binding assays, but still provides functional T cell responses, has been previously identified (22). We therefore assessed the direct binding of biotinylated versions of all the native and citrullinated peptides that did not or did only very weakly displace reference peptides in our competition assays, to plate-bound HLA-DRB1*04:01, *04:04, and *01:01 (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…Epitopes were incubated in increasing concentrations in the presence of plate-bound HLA-DRB1*01, *04:01, or *04:04 and 0.02 μM of the biotinylated competitor epitopes HA 306–318 (PKYVKQNTLKLAT) for HLA-DRB1*04:01 and *01:01, and GAD65 270–285 (LPRLIAFTSEHSHFS) for HLA-DRB1*04:04 (21). Finally, peptide-binding affinity to the three different HLA alleles was assessed in direct binding assays in which N -terminally biotinylated epitopes (GenScript, Piscataway, NJ, USA) were incubated at concentrations from 5 to 0.05 μM with plate-bound relevant HLA-DRB1 molecules in the absence of a competitor peptide (22). The inflection point of the binding curve of a known binding epitope was used as a cutoff to separate weakly binding epitopes from background.…”

Section: Methodsmentioning

confidence: 99%

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Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis

et al. 2016

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Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from α-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified α-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis

et al. 2016

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“…Indeed, it has also been shown that citrullination, depending upon the position it is located, could create a new HLA-DR-restricted functional T cell epitope. In this respect, Chemin et al have shown that the HLA-DRB1*10:01-restricted citrullinated-CII 311–325 epitope is a neo T cell epitope where citrulline is in position P2, where it would affect T cell recognition [62]; Gerstner et al [59] have also made similar observations in the context of an alpha-enolase T cell epitope restricted by DRB1*04:01. Thus, the second potential effect of converting arginine to citrulline in a peptide is that it generates a novel TCR interaction site on the peptide when it is bound and presented by the SE+ HLA-DR molecule.…”

Section: Discussionmentioning

confidence: 96%

Citrullination only infrequently impacts peptide binding to HLA class II MHC

et al. 2017

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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.

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“…The increased likelihood of ACPAs in RA patients with shared epitope haplotypes and the propensity for these HLA‐DR proteins to present citrullinated peptides suggests that CD4 + T‐cell responses to such epitopes actively contribute to disease. Indeed various studies have identified citrullinated vimentin, aggrecan, α ‐enolase, and collagen peptides that elicit functional T‐cell responses in RA patients. Recognition of these citrullinated proteins by T cells has also been documented in HLA transgenic mice .…”

Section: Recognition Of Citrullinated Epitopes In Ramentioning

confidence: 99%

Immune recognition of citrullinated epitopes

Nguyen

James

2016

Immunology

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SummaryConversion of arginine into citrulline is a post-translational modification that is observed in normal physiological processes. However, abnormal citrullination can provoke autoimmunity by generating altered self-epitopes that are specifically targeted by autoantibodies and T cells. In this review we discuss the recognition of citrullinated antigens in human autoimmune diseases and the role that this modification plays in increasing antigenic diversity and circumventing tolerance mechanisms. Early published work demonstrated that citrullinated proteins are specifically targeted by autoantibodies in rheumatoid arthritis and that citrullinated peptides are more readily presented to T cells by arthritis-susceptible HLA class II 'shared epitope' proteins. Emerging data support the relevance of citrullinated epitopes in other autoimmune diseases, including type 1 diabetes and multiple sclerosis, whose susceptible HLA haplotypes also preferentially present citrullinated peptides. In these settings, autoimmune patients have been shown to have elevated responses to citrullinated epitopes derived from tissue-specific antigens. Contrasting evidence implicates autophagy or perforin and complement-mediated membrane attack as inducers of ectopic citrullination. In either case, the peptidyl deiminases responsible for citrullination are activated in response to inflammation or insult, providing a mechanistic link between this posttranslational modification and interactions with the environment and infection. As such, it is likely that immune recognition of citrullinated epitopes also plays a role in pathogen clearance. Indeed, our recent data suggest that responses to citrullinated peptides facilitate recognition of novel influenza strains. Therefore, increased understanding of responses to citrullinated epitopes may provide important insights about the initiation of autoimmunity and recognition of heterologous viruses.

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A Novel HLA–DRB1*10:01–Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis

Cited by 40 publications

References 54 publications

Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis

Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis

Citrullination only infrequently impacts peptide binding to HLA class II MHC

Immune recognition of citrullinated epitopes

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