RESUMO
Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.
Assuntos
Artrite Reumatoide , Linfócitos B , Membrana Sinovial , Humanos , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Análise de Célula Única , Transcriptoma , Plasmócitos/imunologia , Plasmócitos/metabolismo , Idoso , Ativação Linfocitária , AdultoRESUMO
Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent 'superstates' corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.
Assuntos
Artrite Reumatoide , Cromatina , Membrana Sinovial , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/imunologia , Humanos , Cromatina/metabolismo , Cromatina/genética , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/genética , Epigênese Genética , Análise de Célula Única , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fibroblastos/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/genética , Transcrição Gênica , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismoRESUMO
CD8 T cells expressing granzyme K are enriched in synovial tissue from patients with rheumatoid arthritis and in tissues affected by several other autoimmune diseases. The roles these cells play in autoimmune disease is under active investigation, and several recent studies have begun to shed light on this question. Putting this cell type into functional perspective is especially important given their enrichment at the sites of disease. This review summarizes available evidence for the presence of CD8 T cells and other granzyme K-expressing cells in tissues in autoimmune diseases and discusses the effects these cells may have on the pathogenesis of autoimmune conditions.
RESUMO
PURPOSE OF REVIEW: Rheumatoid arthritis is one of the most common rheumatic and autoimmune diseases. While it can affect many different organ systems, RA primarily involves inflammation in the synovium, the tissue that lines joints. Patients with RA exhibit significant clinical heterogeneity in terms of presence or absence of autoantibodies, degree of permanent deformities, and most importantly, treatment response. These clinical characteristics point to heterogeneity in the cellular and molecular pathogenesis of RA, an area that several recent studies have begun to address. RECENT FINDINGS: Single-cell RNA-sequencing initiatives and deeper focused studies have revealed several RA-associated cell populations in synovial tissues, including peripheral helper T cells, autoimmunity-associated B cells (ABCs), and NOTCH3+ sublining fibroblasts. Recent large transcriptional studies and translational clinical trials present frameworks to capture cellular and molecular heterogeneity in RA synovium. Technological developments, such as spatial transcriptomics and machine learning, promise to further elucidate the different types of RA synovitis and the biological mechanisms that characterize them, key elements of precision medicine to optimize patient care and outcomes in RA. This review recaps the findings of those recent studies and puts our current knowledge and future challenges into scientific and clinical perspective.