Tertiary Lymphoid Structures in Rheumatoid Arthritis

• Published in: The American journal of pathology Vol. 185; no. 7; pp. 1935 - 1943
• Main Authors: Noort, Ae R, van Zoest, Katinka P.M, van Baarsen, Lisa G, Maracle, Chrissta X, Helder, Boy, Papazian, Natalie, Romera-Hernandez, Monica, Tak, Paul P, Cupedo, Tom, Tas, Sander W
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.07.2015
• Subjects: Pathology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2015.03.012

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.