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

International Journal of Molecular Sciences

Reza Nadafi¹  Reina E. Mebius¹  Mario Maas²  Krijn P. van Lienden²  Johanna F. Semmelink³  Paul P. Tak³  Janine S. Hähnlein³  Tineke A. de Jong³  Lisa G. M. van Baarsen³  Mary Safy³  Danielle M. Gerlag³  Ester B. M. Remmerswaal⁴  Heidi Wähämaa⁵  Anca I. Catrina⁵ 

[1] Department of Molecular Cell Biology and Immunology, Amsterdam UMC, VU Medical Center, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands;Department of Radiology, Amsterdam UMC, University of Amsterdam, 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;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;Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, 17176 Stockholm, Sweden;

关键词: lymph node stromal cells;    rheumatoid arthritis;    tolerance;    autoimmunity;   

DOI  :  10.3390/ijms21165713

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown