Tertiary Lymphoid Structures in Rheumatoid Arthritis: NF-κB-Inducing Kinase-Positive Endothelial Cells as Central Players.

Abstract

Tertiary lymphoid structures (TLSs) in chronic inflammation, including rheumatoid arthritis (RA) synovial tissue (ST), often contain high endothelial venules and follicular dendritic cells (FDCs). Endothelial cell (EC)-specific lymphotoxin β (LTβ) receptor signaling is critical for the formation of lymph nodes and high endothelial venules. FDCs arise from perivascular platelet-derived growth factor receptor β(+) precursor cells (preFDCs) that require specific group 3 innate lymphoid cells (ILC3s) and LTβ for their expansion. Previously, we showed that RA ST contains ECs that express NF-κB-inducing kinase (NIK), which is pivotal in LTβ-induced noncanonical NF-κB signaling. We studied the relation between NIK(+) ECs, (pre)FDCs, and ILC3s with respect to TLSs in RA ST. TLS(+) tissues exhibited a significantly increased expression of genes involved in noncanonical NF-κB signaling, including NIK, and immunohistochemical analysis revealed that NIK was almost exclusively expressed by ECs. ILC3s were present in human RA ST in very low numbers, but not differentially in TLS(+) tissues. In contrast, TLS(+) tissues contained significantly more NIK(+) ECs and perivascular platelet-derived growth factor receptor β(+) preFDCs, which correlated significantly with the quantity of FDCs. We established a strong link between NIK(+) ECs, (pre)FDCs, and the presence of TLSs, indicating that NIK(+) ECs may not only be important orchestrators of lymph node development but also contribute to the formation of TLSs in chronic inflammation.

• Authors: Ae R Noort, Katinka P M van Zoest, Lisa G van Baarsen, Chrissta X Maracle, Boy Helder, Natalie Papazian, Monica Romera-Hernandez, Paul P Tak, Tom Cupedo, Sander W Tas
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 7 Pg. 1935-43 (Jul 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25963989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• LTBR protein, human
• Lymphotoxin beta Receptor
• NF-kappa B
• Protein Serine-Threonine Kinases
• NF-kappa B kinase

Topics

• Adult
• Aged
• Arthritis, Rheumatoid (immunology, metabolism, pathology)
• Endothelial Cells (enzymology, metabolism)
• Female
• Humans
• Inflammation
• Lymphoid Tissue (immunology, metabolism, pathology)
• Lymphotoxin beta Receptor (metabolism)
• Male
• Middle Aged
• NF-kappa B (metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction
• Synovial Membrane (immunology, metabolism, pathology)