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. 2011 Mar;10(3):M110.002477.
doi: 10.1074/mcp.M110.002477. Epub 2010 Nov 16.

Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or antibiotic-refractory Lyme arthritis

Robert J Seward  1 , Elise E Drouin, Allen C Steere, Catherine E Costello
Affiliations

Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or antibiotic-refractory Lyme arthritis

Robert J Seward et al. Mol Cell Proteomics. 2011 Mar.

Abstract

Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220-464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions.

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Figures

Fig. 1.
Fig. 1.
Characterization of HLA-DR-presented peptides based upon cellular locations and biological functions of source proteins of peptides. The primary cellular location (A) and the primary biological function (B) are shown for each protein as determined using the Human Protein Reference Database (www.hprd.org).
Fig. 2.
Fig. 2.
Characterization of HLA-DR-presented peptides based upon length. (A) The percentage of peptides with a given amino acid residue length is shown for the 1,427 peptides identified in the four patients' samples. (B) Proline frequency at N2 and C2 in identified naturally MHC-presented peptides. Proline residues were observed to occur in (250/1427) × 100 = 17.5% of the sites, whereas the proline abundance in human proteins is 6.4%.
Fig. 3.
Fig. 3.
Characterization of HLA-DR-presented peptides based upon predicted binding to patients' HLA-DR molecules. The number of HLA-DR-peptides predicted to bind that patient's HLA-DR molecules is shown. N.A., not applicable.
Fig. 4.
Fig. 4.
Sequence locations of epitopes observed for seven proteins that are highly represented among peptides found in synovial tissues of Patients 1–4 (1, LA1; 2, LA2; 3, RA1; 4, RA2).
Fig. 5.
Fig. 5.
LTQ-Orbitrap CID tandem mass spectra of two overlapping peptides derived from cathepsin S and post-translationally modified with disulfide-linked cysteine. A, KTGKLVSLSAQNLVDC-Cys [M + 3H]3+ m/z 598.98, neutral mass 1793.90 Da. B, LKTGKLVSLSAQNLVDC-Cys [M + 3H]3+ m/z 636.67, neutral mass 1906.98 Da. Because the difference between the two peptides is at the amino terminus, the two b-series of fragments exhibit a mass shift consistent with the presence of the additional amino-terminal Leu residue that corresponds to the difference between the two molecular masses, whereas the y-series show common fragments.
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