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


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Authors
Hähnlein, Janine S 
Semmelink, Johanna F 
Remmerswaal, Ester BM 
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.

Description
Keywords
autoimmunity, lymph node stromal cells, rheumatoid arthritis, tolerance, Adult, Animals, Anti-Citrullinated Protein Antibodies, Arthritis, Rheumatoid, B7-H1 Antigen, Cells, Cultured, Female, HLA-DR Antigens, Humans, Lymph Nodes, Male, Mice, Middle Aged, Peripheral Tolerance, Stromal Cells
Journal Title
Int J Mol Sci
Conference Name
Journal ISSN
1661-6596
1422-0067
Volume Title
21
Publisher
MDPI AG
Sponsorship
ZonMw (91612109 and 91718371)
Innovative Medicines Initiative (115142)
FP7 Health (FP7-HEALTH-F2-2012-305549)