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

Kaaij MH, Rip J, Jeucken KC, Kan YY, van Rooijen CC, Saris J, Pots D, Frey S, Grootjans J, Schett G, van Duivenvoorde LM, Nolte MA, Hendriks RW, Corneth OB, van Hamburg JP, Baeten DL, Tas SW (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Journal of Immunology American Association of Immunologists

Book Volume: 207

Pages Range: 2337-2346

Journal Issue: 9

DOI: 10.4049/jimmunol.2100512

Abstract

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.

Authors with CRIS profile

Silke Frey Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III

Involved external institutions

Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra NL Netherlands (NL) Erasmus University Medical Center (MC) NL Netherlands (NL)

How to cite

APA:

Kaaij, M.H., Rip, J., Jeucken, K.C., Kan, Y.Y., van Rooijen, C.C., Saris, J.,... Tas, S.W. (2021). Overexpression of transmembrane TNF drives development of ectopic lymphoid structures in the bone marrow and B cell lineage alterations in experimental spondyloarthritis. Journal of Immunology, 207(9), 2337-2346. https://dx.doi.org/10.4049/jimmunol.2100512

MLA:

Kaaij, Merlijn H., et al. "Overexpression of transmembrane TNF drives development of ectopic lymphoid structures in the bone marrow and B cell lineage alterations in experimental spondyloarthritis." Journal of Immunology 207.9 (2021): 2337-2346.

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