Abstract
ObjectivesWe explored histological and transcriptomic profiles of paired synovial biopsies from rheumatoid arthritis (RA) patients, in order to assess homogeneity in synovial tissue at the individual level.MethodsSynovial biopsies were performed simultaneously in one small and one large joint per patient using needle-arthroscopy for the knee and ultrasound-guided biopsy for the hand or wrist. Synovium from individuals with osteoarthritis was used as controls. Paraffin-embedded samples were stained for CD3, CD20, and CD68. Total RNA was hybridized on high-density microarrays. TCRB variable sequences were obtained from synovial and blood RNA samples.ResultsTwenty paired biopsies from 10 RA patients with active disease were analyzed. Semi-quantification of histological markers showed a positive correlation for synovial hyperplasia, inflammatory infiltrates and CD3-positive T cells between pairs. Pairwise comparison of transcriptomic profiles showed similar expression of RA-related molecular pathways (TCR signaling, T cell costimulation and response to TNFα). T cells clonotypes were enriched in all but one joints compared to blood, regardless of the magnitude of T cell infiltration. Enriched clonotypes were shared between pairs (23–100%), but this was less the case in pairs of joints displaying weaker T cell signatures and more pronounced germinal center-like transcriptomic profiles.ConclusionCellular and molecular alterations in RA synovitis are similar between small and large joints from the same patient. Interindividual differences in magnitude of T cell infiltrates and distribution of enriched T cell clonotypes support the concept of distinct synovial pathotypes in RA that are associated with systemic versus local antigen-driven activation of T cells.
Highlights
Synovitis in rheumatoid arthritis (RA) is characterized by alterations in synovial architecture such as hyperplasia of the synovial lining membrane, hypervascularity and infiltration of the sublining by mononuclear cells
Several studies were performed in order to understand the mechanisms driving heterogeneity in histological, cellular and molecular changes in rheumatoid synovitis and investigate whether synovial cellular and molecular patterns can be linked to clinical outcomes [5,6,7,8,9,10,11]
We and others reported that disease activity correlates with the expression of T cell- and myeloid-related transcripts in RA synovitis [2, 6, 11]
Summary
Synovitis in rheumatoid arthritis (RA) is characterized by alterations in synovial architecture such as hyperplasia of the synovial lining membrane, hypervascularity and infiltration of the sublining by mononuclear cells These modifications are associated with changes in the activation patterns of infiltrating and resident cells, as indicated by recent molecular studies on whole biopsies or single synovial cells [1,2,3,4]. Several studies were performed in order to understand the mechanisms driving heterogeneity in histological, cellular and molecular changes in rheumatoid synovitis and investigate whether synovial cellular and molecular patterns can be linked to clinical outcomes [5,6,7,8,9,10,11] Clinical variables such as disease activity, disease duration, ACPA status or response to specific therapies were associated with variations in cellular populations and molecular profiles in RA synovial biopsies [12]. The stability of these pathotypes over time, and whether they reflect the presence of distinct endotypes (i.e. subgroups defined by different functional mechanisms) or extremities of a continuous spectrum, is still under investigation
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