B cells in rheumatoid arthritis synovial tissues encode focused antibody repertoires that include antibodies that stimulate macrophage TNF-α production

Elliott, Serra E.; Kongpachith, Sarah; Lingampalli, Nithya; Adamska, Julia Z.; Cannon, Bryan J.; Blum, Lisa K.; Bloom, Michelle S.; Henkel, Matthew; McGeachy, Mandy J.; Moreland, Larry W.; Robinson, William H.

doi:10.1016/j.clim.2020.108360

Cited by 15 publications

(13 citation statements)

References 41 publications

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“…This is consistent with a trajectory of B cell activation whereby blood B cells are recruited to the synovium pre-flare, activated within the synovial microenvironment to express NR4A, and then possibly re-circulate during flare. Re-circulation of B cells between the synovium and the periphery is also supported by a recent publication demonstrating shared clonal families between these compartments in RA (64). The origin of the B cells increasing in the blood pre-flare remains to be determined.…”

Section: Discussionmentioning

confidence: 75%

Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression

Meednu

Rangel-Moreno

Zhang

et al. 2021

Preprint

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Ectopic lymphoid structures (ELS) are present in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and the role of in situ synovial B cell differentiation and selection in disease are not well understood. Here, we identified a B cell population in the synovium characterized by expression of NR4A1-3, a family of orphan nuclear receptors, that is highly enriched at both early and late stages of RA. NR4A B cells are rare in healthy peripheral blood, RA blood, and SLE kidney, but share markers with blood transcriptomic signatures that peak during RA disease flare. Using combined single cell transcriptomics and B cell receptor (BCR) sequencing, we demonstrate that NR4A synovial B cells have an activated transcriptomic profile that significantly overlaps with germinal center (GC) light zone (LZ) B cells and an accrual of somatic hypermutation that correlates with loss of naive B cell status. NR4A B cells uniquely co-express lymphotoxin β and IL6, supporting important functions in ELS promotion and pro-inflammatory cytokine production. The presence of shared clones in this activated B cell state, NR4A expressing synovial plasma cells (PC), and CCR6+ memory B cell (MBC) precursors further points to in situ differentiation. NR4A1 was expressed at the protein level in RA synovial B cells and PC, was high in tonsil GC B cells with a LZ-DZ intermediate phenotype, and was rapidly induced at both the RNA and protein level upon activation through the BCR. Taken together, we identified a dynamic progression of B cell activation in RA synovial ELS, with NR4A as a read-out of likely antigen activation and local adaptive immune responses.

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Section: Discussionmentioning

confidence: 75%

Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression

Meednu

Rangel-Moreno

Zhang

et al. 2021

Preprint

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“…There was limited overlap between PB and synovial BCR clones, further suggesting their local expansion [27]. On the other hand, Elliot showed certain extent of clonal relationship in BCR between PB and synovial compartments, suggesting B cell trafficking between PB and synovium, although synovial samples showed greater extent of clonal expansion [28]. Some studies established ACPA-producing B cell clones from the joint, although it is difficult to draw conclusion on the difference from those in PB due to small number of samples.…”

Section: Antibody Production By Joint-infiltrating B Cells In Ramentioning

confidence: 96%

“…They differed from non-ACPA clones in the expression of CD40 and C5a receptor 1 [30]. Lastly, Elliot et al reported TNF-a production from macrophages stimulated with immune complex that contain recombinant ACPA cloned from RASF [28].…”

Section: Antibody Production By Joint-infiltrating B Cells In Ramentioning

confidence: 99%

Adaptive immunity in the joint of rheumatoid arthritis

Yamada

2021

Immunological Medicine

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Adaptive immunity plays central roles in the pathogenesis of rheumatoid arthritis (RA), as it is regarded as an autoimmune disease. Clinical investigations revealed infiltrations of B cells in the synovium, especially those with ectopic lymphoid neogenesis, associate with disease severity. While some B cells in the synovium differentiate into plasma cells producing autoantibodies such as anti-citrullinated protein antibody, others differentiate into effector B cells producing proinflammatory cytokines and expressing RANKL. Synovial B cells might also be important as antigen-presenting cells. Synovial T cells are implicated in the induction of antibody production as well as local inflammation. In the former, a recently identified CD4 T cell subset, peripheral helper T (Tph), which is characterized by the expression of PD-1 and production of CXCL13 and IL-21, is implicated, while the latter might be mediated by Th1-like CD4 T cell subsets that can produce multiple proinflammatory cytokines, including IFN-c, TNF-a, and GM-CSF, and express cytotoxic molecules, such as perforin, granzymes and granulysin. CD8 T cells in the synovium are able to produce large amount of IFN-c. However, the involvement of those lymphocytes in the pathogenesis of RA still awaits verification. Their antigen-specificity also needs to be clarified.

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“…As the culprits responsible for maturing and generating ACPAs, B cells undeniably play a destructive role in RA pathogenesis and in sustaining chronic disease [27,33,34,151,152]. As such, depletion of B cells in RA has seen therapeutic effects [65,153].…”

Section: B Cellsmentioning

confidence: 99%

Biomaterial-based immunotherapeutic strategies for rheumatoid arthritis

Lewis

2021

Drug Deliv. and Transl. Res.

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B cells in rheumatoid arthritis synovial tissues encode focused antibody repertoires that include antibodies that stimulate macrophage TNF-α production

Cited by 15 publications

References 41 publications

Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression

Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression

Adaptive immunity in the joint of rheumatoid arthritis

Biomaterial-based immunotherapeutic strategies for rheumatoid arthritis

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