Dataset Information

Multitiered proteome analysis displays the hyperpermeability of the rheumatoid synovial compartment for plasma proteins

ABSTRACT: Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and cartilage/bone destruction. RA affects the synovial joints, the synovial lining and consequently the permeability of the synovium. As the latter is of central relevance for the distribution of systemically delivered therapeutics into synovial fluid (SF), we here assessed the protein composition of paired plasma and SF of patients diagnosed with RA at three distinct levels of depth using mass spectrometric approaches: the “total” proteome, the “total” IgG1 antibody repertoire and the RA-specific ACPA IgG1 autoantibody repertoire. The SF proteome was dominated by >150 plasma proteins, and we additionally detected several cartilage- and neutrophil-derived proteins of lower abundance. Strikingly, the plasma proteins were not only qualitatively reflected in SF but also quantitatively, independent of their size and/or other biochemical features. Also the synovial “total” IgG1 and autoreactive ACPA IgG1 repertoire highly resembled the IgG1 repertoires detected in plasma within the same patient. Our comprehensive multilayer data thus reveals that the proteome, including the dominant, most abundant (auto)antibody clones, present in SF of RA patients is a direct reflection of the proteome present in blood, spiked by the local (immune) processes within the RA joint. We thus conclude that proteins directly pass from blood into SF of these joints without substantial filtration bias. These findings thereby not only exemplify the use of in-depth multilayer proteome analyses to revisit basic concepts underlying RA pathology and to monitor the local (immune) processes destructive to cartilage, but also provide evidence indicating that (protein-based) therapeutics may equally enter SF of swollen joints and that pharmacokinetic analyses of such therapeutics in blood are directly relevant to the synovial compartment.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma, Rheumatoid Arthritis Disease Specific Synovial Fluid

SUBMITTER: Sofia Kalaidopoulou Nteak

LAB HEAD: Albert J.

PROVIDER: PXD054336 | Pride | 2025-01-21

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	20231211_RA_wo_ctrl-lib.predicted.speclib	Other
	20231211_RA_wo_ctrl-lib.tsv	Tabular
	20231211_RA_wo_ctrl-lib.tsv.speclib	Tabular
	20231211_RA_wo_ctrl_report-first-pass.gg_matrix.tsv	Tabular
	20231211_RA_wo_ctrl_report-first-pass.pg_matrix.tsv	Tabular

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Publications

Multi-tiered proteome analysis displays the hyper-permeability of the rheumatoid synovial compartment for plasma proteins.

Stork Eva Maria EM Nteak Sofia Kalaidopoulou SK van Rijswijck Danique M H DMH Damen J Mirjam A JMA Scherer Hans Ulrich HU Toes Rene E M REM Bondt Albert A Huizinga Tom W J TWJ Heck Albert J R AJR

Molecular & cellular proteomics : MCP 20241231

Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and cartilage/bone destruction. RA affects the synovial joints, the synovial lining and the permeability of the synovium. As the latter is of central relevance for the distribution of systemically delivered therapeutics into synovial fluid (SF), we here assessed the protein composition of paired plasma and SF of patients diagnosed with RA at three distinct levels of depth using mass spectrometric approaches: the "total" proteome, ...[more]

PMID: 39746544

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Project description:HLA-DR molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory arthritides, including in rheumatoid arthritis (RA) and Lyme arthritis (LA). In the current study, we identified HLA-DR-presented self-peptides (T cell epitopes) in ST, synovial fluid mononuclear cells (SF), and peripheral blood mononuclear cells (PB) from five patients with RA and eight with LA. Altogether, from 22 samples, 1,532 non-redundant HLA-DR-presented peptides were identified that were derived from 778 source proteins. Moreover, as the study progressed, application of newer, high sensitivity LC-MS instruments resulted in the identification of larger numbers of HLA-DR-presented peptides. Surprisingly, the source proteins for HLA-DR-presented peptides were as likely to have intracellular as extracellular locations. Although the number of peptides identified was greater in ST than in SF or PB, 68% of the peptides identified in SF were found in ST, and 55% of the peptides in PB were found in ST. Two RA patients had the same HLA-DR genotype (DRB1*0401 and 0101), and 44% of the peptides identified in these two patients were the same. In contrast, among the patients with RA or LA who had no shared HLA-DR alleles, only 6% of the peptides were the same. In the RA patients, HLA-DR-presented peptides were identified from source proteins that are thought to serve as potential autoantigens: collagen, enolase, fibrinogen, fibronectin, immunoglobulin and vimentin. Interestingly, peptides from these same source proteins were also commonly found in LA patients. However, citrullinated T cell epitopes were not identified in any patient. Thus, LC-MS/MS techniques are now sensitive enough to identify large numbers of T cell epitopes from tissue or fluids in individual patients. Importantly, analysis of SF or PB allowed us to identify a broader range of HLA-DR-presented self-peptides from individual patients and from patients seen earlier in the disease.