In Rheumatoid Arthritis, Synovitis at Different Inflammatory Sites Is Dominated by Shared but Patient-Specific T Cell Clones

Abstract

Genetic and immunological evidence clearly points to a role for T cells in the pathogenesis of rheumatoid arthritis (RA). Selective targeting of such disease-associated T cell clones might be highly effective while having few side effects. However, such selective targeting may only be feasible if the same T cell clones dominate the immune response at different sites of inflammation. We leveraged high-throughput technology to quantitatively assess whether different T cell clones dominate the inflammatory infiltrate at various sites of inflammation in this prototypic autoimmune disease. In 13 RA patients, we performed quantitative next-generation sequencing-based human TCRβ repertoire analysis in simultaneously obtained samples from inflamed synovial tissue (ST) from distinct locations within one joint, from multiple joints, and from synovial fluid (SF) and peripheral blood (PB). Identical TCRβ clones dominate inflammatory responses in ST samples taken from different locations within a single joint and when sampled in different joints. Although overall ST-SF overlap was comparable to higher ST-ST values, the overlap in dominant TCRβ clones in ST-SF comparisons was much lower than ST-ST and comparable to the low ST-PB overlap. In individual RA patients, a limited number of TCRβ clones dominate the immune response in the inflamed ST regardless of the location within a joint and which joint undergoes biopsy; in contrast, there is limited overlap of ST with SF or PB TCR repertoires. This limited breadth of the T cell response in ST of the individual RA patient indicates that development of immunotherapies that selectively modulate dominant T cell responses might be feasible.

Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients

“…Furthermore, the demonstration of a significant difference in pathotype frequency between joints highlights the importance of techniques such as US-guided synovial biopsy to enable unbiased recruitment of patients, through capacity to sample a wide variety of joints, and thus ensure representative sampling. While in our study we did not perform simultaneous biopsies of different joints in the same patient, so cannot address per se whether synovial pathotype/molecular signatures are stable between joints of the same patient, it important to note that previous studies have documented stable cellular infiltrates24 and specific T-cell oligoclonal expansions25 between joints within the same individuals, supporting the notion of a uniform pathology at individual patient level across multiple joints.…”

Dendritic cells, T cells and their interaction in rheumatoid arthritis

“…These findings suggest the contribution of a limited number of expanded T cell clones to early RA pathogenesis, and highlight that clonotypical analysis of ST harvested from patients with preclinical RA may be fruitful. Of the oligoclonal expansions found in a recent study of RA ST, the same expanded TCRβ clones dominated at different locations within the single inflamed joint as well as in different joints when compared to the paired PB repertoire [89]. These findings suggest that there is widespread TCR recognition of the same antigens presented by APCs in ST.…”

“…Furthermore, the degree of clonal dominance (exclusive expansion of a few clones) observed in recently diagnosed RA patients was significantly greater than in established RA patients [88]. Of the oligoclonal expansions found in a recent study of RA ST, the same expanded TCRβ clones dominated at different locations within the single inflamed joint as well as in different joints when compared to the paired PB repertoire [89]. Of the oligoclonal expansions found in a recent study of RA ST, the same expanded TCRβ clones dominated at different locations within the single inflamed joint as well as in different joints when compared to the paired PB repertoire [89].…”

TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

“…RA The biased use of the Vα-gene and Vβ-gene has been reported in T cells from synovial fluid; however, the significantly different use of any V-gene was not identified in the peripheral blood 21,43,44 . In this study, we found that the use of 11 V-genes and 1 J-gene by the TCRB was different in certain subsets between RA and HC groups.…”

“…Notwithstanding these controversial findings, most studies have demonstrated that the T cells from RA patients respond through clonal expansion in the synovia and/or peripheral blood 11,13,14,15,16,17,18,19,20,21 .…”