TCR repertoire profiling revealed antigen-driven CD8+ T cell clonal groups shared in synovial fluid of patients with spondyloarthritis

Abstract

Spondyloarthritis (SpA) comprises a number of inflammatory rheumatic diseases with overlapping clinical manifestations. Strong association with several HLA-I alleles and T cell infiltration into an inflamed joint suggest involvement of T cells in SpA pathogenesis. In this study, we performed high-throughput T cell repertoire profiling of synovial fluid (SF) and peripheral blood (PB) samples collected from a large cohort of SpA patients. We showed that synovial fluid is enriched with expanded T cell clones that are shared between patients with similar HLA genotypes and persist during recurrent synovitis. Using an algorithm for identification of TCRs involved in immune response we discovered several antigen-driven CD8+ clonal groups associated with risk HLA-B*27 or HLA-B*38 alleles. We further show that these clonal groups were enriched in SF and had higher frequency in PB of SpA patients vs healthy donors, implying their relevance to SpA pathogenesis. Several of the groups were shared among patients with different SpAs that suggests a common immunopathological mechanism of the diseases. In summary, our results provide evidence for the role of specific CD8+ T cell clones in pathogenesis of SpA.

Virus-Associated CD8 + T-Cells Are Not Activated Through Antigen-Mediated Interaction Inside Atherosclerotic Lesions

“…A previously published dataset containing TCRβ sequences from synovial fluid and patient-matched blood samples from psoriatic arthritis patients was utilized to evaluate the ratio of virus-associated TCRβ sequences between circulation and the site of inflammation. 33 Interestingly, virus-associated T-cells did not specifically home toward the inflamed synovium, indicating that virus-associated CD8 + T-cells do not accumulate at every site of chronic inflammation (Figure S2).…”

“…To evaluate the proportion of virus-associated CD8 + T-cells at another site of chronic inflammation, a previously published dataset containing TCRβ sequencing data from synovial fluid and blood samples from psoriatic arthritis patients was utilized (data availability: ArrayExpress E-MTAB-11498). 33 Viral association of the TCRβ was determined as described above.…”

Uncovering the Underworld of Axial Spondyloarthritis

“…Moreover, the same clonotypes may be found in the synovial fluid months after the first evaluation, underlining that they can persist in this tissue as resident T cells. Several TCRβ motifs have been identified to be associated with SpA risk HLA-I alleles, suggesting HLA-I-driven antigenic selection of T cells, also reproducible in SF samples from different patients [ 105 ]. In addition, CD8 + TCR of AS patients also showed a possible involvement of viral antigens, based on a revealed expansion of Epstein–Barr virus and Cytomegalovirus specific clonotypes [ 26 ].…”

Effectiveness and safety of BCD180, anti-TRBV9⁺ T-lymphocytes monoclonal antibody in patients with active radiographic axial spondyloarthritis: 36-week results of double-blind randomized placebo-controlled phase II clinical study ELEFTA

“…При исследовании репертуара Т-клеточных рецепторов периферической крови у носителей HLA-B27 с аксСпА был определен характерный аминокислотный мотив CDR3 участка бета-цепи, несущей определенный генный сегмент -TRBV9 [10,11]. Эффекторные CD8 + Т-лимфоциты, несущие такие Т-клеточные рецепторы, присутствуют в периферической крови пациентов с аксСпА в значимо большем количестве по сравнению со здоровыми носителями HLA-B27, а также по результатам анализа репертуара более представлены в синовиальной жидкости, где реализуется иммуновоспалительный процесс [12]. Дальнейшие исследования идентифицировали вероятные пептидные мишени таких Т-клеточных рецепторов, включая бактериальные антигены, которые могут служить инициальной причиной развития Т-клеточного ответа (артритогенные пептиды), и собственные антигены человека, которые могут распознаваться такими Т-лимфоцитами в контексте HLA-B27 в результате кросс-реактивного взаимодействия [13].…”

“…Evgeny l. nasonov 1,2 , vadim i. mazurov 3 , alexander m. lila 1,4 , tatiana v. dubinina 1 , inna z. gaydukova 3,5 , svetlana a. lapshina 6,7 , alesya a. klimenko 8,9 , dmitrii v. somov 9 , sergey a. lukianov 9 , dmitry m. chudakov 9 , ivan v. zvyagin 9 , olga v. Britanova 9 , maxim a. korolev 10 , diana g. krechikova 11 , alexander a. kastanayan 12 , larisa v. Eliseeva 13 , Ruzana R. samigullina 2 , tatyana v. povarova 14 , olga v. antipova 15 , svetlana a. smakotina 16,17 , valentina n. soboleva 18 , olga B. nesmeyanova 19 , tatiana v. plaksina 20 , diana i. abdulganieva 6,7 , nikolay f. soroka 21 , irina B. vinogradova 22 , andrey p. Rebrov 23 , tatiana v. kropotina 24 , alexey l. maslyanskiy 25 , arina v. zinkinaorikhan 26 , yulia n. lin'kova 26 , polina s. pukhtinskaia 26 , maria a. morozova 26 , galina a. vinderskaya 26 the aim -to evaluate the clinical effectiveness, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of seniprutug (BCD-180) in patients with radiographic active axial spondyloarthritis (r-axSpA, or ankylosing spondylitis). subjects and methods.…”