Overexpression of transmembrane TNF drives development of ectopic lymphoid structures in the bone marrow and B cell lineage alterations in experimental spondyloarthritis

Merlijn H. Kaaij, Jasper Rip, Kim C.M. Jeucken, Yik Y. Kan, Charlotte C.N. van Rooijen, Job Saris, Desiree Pots, Silke Frey, Joep Grootjans, Georg Schett, Leonie M. van Duivenvoorde, Martijn A. Nolte, Rudi W. Hendriks, Odilia B.J. Corneth, Jan Piet van Hamburg, Dominique L.P. Baeten, Sander W. Tas*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


TNF is important in immune-mediated inflammatory diseases, including spondyloarthritis (SpA). Transgenic (tg) mice overexpressing transmembrane TNF (tmTNF) develop features resembling human SpA. Furthermore, both tmTNF tg mice and SpA patients develop ectopic lymphoid aggregates, but it is unclear whether these contribute to pathology. Therefore, we characterized the lymphoid aggregates in detail and studied potential alterations in the B and T cell lineage in tmTNF tg mice. Lymphoid aggregates developed in bone marrow (BM) of vertebrae and near the ankle joints prior to the first SpA features and displayed characteristics of ectopic lymphoid structures (ELS) including presence of B cells, T cells, germinal centers, and high endothelial venules. Detailed flow cytometric analyses demonstrated more germinal center B cells with increased CD80 and CD86 expression, along with significantly more T follicular helper, T follicular regulatory, and T regulatory cells in tmTNF tg BM compared with non-tg controls. Furthermore, tmTNF tg mice exhibited increased IgA serum levels and significantly more IgA+ plasma cells in the BM, whereas IgA+ plasma cells in the gut were not significantly increased. In tmTNF tg 3 TNF-RI2/2 mice, ELS were absent, consistent with reduced disease symptoms, whereas in tmTNF tg 3 TNF-RII2/2 mice, ELS and clinical symptoms were still present. Collectively, these data show that tmTNF overexpression in mice results in osteitis and ELS formation in BM, which may account for the increased serum IgA levels that are also observed in human SpA. These effects are mainly dependent on TNF-RI signaling and may underlie important aspects of SpA pathology.

Original languageEnglish
Pages (from-to)2337-2346
Number of pages10
JournalJournal of Immunology
Issue number9
Publication statusPublished - 1 Nov 2021

Bibliographical note

Funding Information:
This work was supported by the ReumaNederland (Grant 15-2-401). We thank Daisy I. Picavet (Amsterdam University Medical Center), Susanne Adam (Friedrich-Alexander University Erlangen-N?urnberg and Universit?atsklinikum Erlangen Friedrich-Alexander University Erlangen-Nurnberg), ? Marjolein J. W. de Bruijn, Jennifer A. C. van Hulst and Stefan F.H. Neys (Erasmus University Medical Center, Rotterdam) for expert technical assistance. We also thank George Kollias for providing the tmTNF tg mice.

Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc. All rights reserved.


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