Human Lymph Node Stromal Cells Have the Machinery to Regulate Peripheral Tolerance during Health and Rheumatoid Arthritis

International Journal of Molecular Sciences, vol. 21, pp. 5713

Abstract

Background: In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA. Method: Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation (n = 15). Results: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients. Conclusion: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.

Authors 14

1. Janine S. Hähnlein

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands

   Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

2. Reza Nadafi Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Department of Molecular Cell Biology and Immunology, Amsterdam UMC, VU Medical Center, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands

3. Tineke A. de Jong

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands

   Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

4. Johanna F. Semmelink

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands

   Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

5. Ester B. M. Remmerswaal

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Renal Transplant Unit, Division of Internal Medicine and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

6. Mary Safy

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

7. Krijn P. van Lienden

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Department of Radiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

8. Mario M. Maas

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Department of Radiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

9. Daniëlle M. Gerlag

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

10. Paul P. Tak

    University of Cambridge · Ghent University · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

    Internal Medicine, Cambridge University, Cambridge, CB2 1TN, UK

    Kintai Therapeutics, Cambridge, MA 02140, USA

    Rheumatology, Ghent University, 9000 Ghent, Belgium

11. Reina E. Mebius

    Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Department of Molecular Cell Biology and Immunology, Amsterdam UMC, VU Medical Center, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands

12. Heidi Wähämaa

    Karolinska University Hospital · Karolinska Institutet

    Affiliation as printed

    Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, 17176 Stockholm, Sweden

13. Anca I. Catrina

    Karolinska University Hospital · Karolinska Institutet

    Affiliation as printed

    Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, 17176 Stockholm, Sweden

14. Lisa G. M. van Baarsen corresponding

    Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, 1105 AZ Amsterdam, The Netherlands

    Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands