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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 and Sander W. Tas
J Immunol November 1, 2021, 207 (9) 2337-2346; DOI: https://doi.org/10.4049/jimmunol.2100512
Merlijn H. Kaaij
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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  • ORCID record for Merlijn H. Kaaij
Jasper Rip
‡Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands;
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Kim C. M. Jeucken
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Yik Y. Kan
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Charlotte C. N. van Rooijen
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Job Saris
§Department of Gastroenterology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
¶Tytgat Institute for Intestinal and Liver Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Desiree Pots
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Silke Frey
‖Department of Internal Medicine 3, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, Germany; and
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Joep Grootjans
§Department of Gastroenterology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
¶Tytgat Institute for Intestinal and Liver Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Georg Schett
‖Department of Internal Medicine 3, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, Germany; and
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Leonie M. van Duivenvoorde
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Martijn A. Nolte
#Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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Rudi W. Hendriks
‡Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands;
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Odilia B. J. Corneth
‡Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands;
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Jan Piet van Hamburg
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Dominique L. P. Baeten
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Sander W. Tas
*Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
†Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
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Key Points

  • tmTNF overexpression causes formation of ELS.

  • ELS are located in BM next to inflammatory joint and spine lesions.

  • ELS formation is accompanied by increased IgA class switching.

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 × TNF-RI−/− mice, ELS were absent, consistent with reduced disease symptoms, whereas in tmTNF tg × TNF-RII−/− 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.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by the ReumaNederland (Grant 15-2-401).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    BM
    bone marrow
    ELS
    ectopic lymphoid structure
    GC
    germinal center
    HEV
    high endothelial venule
    hTNF
    human TNF
    IBD
    inflammatory bowel disease
    IF
    immunofluorescence
    PC
    plasma cell
    PNA
    peanut agglutinin
    RA
    rheumatoid arthritis
    SpA
    spondyloarthritis
    sTNF
    soluble TNF
    Tfh
    T follicular helper
    tg
    transgenic
    tmTNF
    transmembrane TNF
    Tfr
    T follicular regulatory
    Treg
    T regulatory cell

  • Received May 28, 2021.
  • Accepted August 22, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 207 (9)
The Journal of Immunology
Vol. 207, Issue 9
1 Nov 2021
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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
The Journal of Immunology November 1, 2021, 207 (9) 2337-2346; DOI: 10.4049/jimmunol.2100512

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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
The Journal of Immunology November 1, 2021, 207 (9) 2337-2346; DOI: 10.4049/jimmunol.2100512
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