| Autor: |
H. Mark Kenney, Javier Rangel-Moreno, Yue Peng, Kiana L. Chen, Jennifer Bruno, Abdul Embong, Elizabeth Pritchett, Jeffrey I. Fox, Sally Quataert, Gowrishankar Muthukrishnan, Ronald W. Wood, Benjamin D. Korman, Jennifer H. Anolik, Lianping Xing, Christopher T. Ritchlin, Edward M. Schwarz, Chia-Lung Wu |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.10.27.514103 |
| Popis: |
Defective lymphatic drainage and B-cell translocation into joint-draining lymph node sinuses are pathogenic phenomena in patients with severe rheumatoid arthritis (RA). However, the molecular mechanisms underlying this lymphatic dysfunction remain poorly understood. Here, by utilizing spatial and single-cell transcriptomics in tumor necrosis factor transgenic (TNF-Tg) mice, we characterized functional genomic changes in popliteal lymph nodes (PLNs) of “Early” and “Advanced” RA to determine the mechanisms orchestrating B-cell differentiation. We first show thatIghg2bexpression localized to Marco+sinuses and negatively correlated with bone volumes in ipsilateral joints. We further reveal that Advanced PLNs exhibited a concomitant accumulation of iron-laden macrophages and T-cells. Mechanistically, crosstalk between ALCAM+macrophages and CD6+T-cells was identified as a co-stimulatory pathway promoting IgG2b class-switching. These findings were validated by immunohistochemistry, flow cytometry, ELISPOT, and clinical correlates. Collectively, we propose that ALCAM-CD6 co-stimulation activates T cells, initiating IgG2b class-switching and plasma cell differentiation in RA flare. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
