Tertiary Lymphoid Structures in Rheumatoid Arthritis NF-kappa B-Inducing Kinase-Positive Endothelial Cells as Central Players

AR Noort, KPM van Zoest, LG van Baarsen, CX Maracle, B Helder, Natalie Papazian, Monica Romera Hernandez, PP Tak, Tom Cupedo, SW Tas

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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 beta (LT beta) receptor signaling is critical for the formation of lymph nodes and high endothelial venules. FDCs arise from perivascular platelet-derived growth factor receptor beta(+) precursor cells (preFDCs) that require specific group 3 innate lymphoid cells (ILC3s) and LT beta for their expansion. Previously, we showed that RA ST contains ECs that express NF-kappa B-inducing kinase (NIK), which is pivotal in LT beta-induced noncanonical NF-kappa B 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-kappa B 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 beta(+) 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.
Original languageUndefined/Unknown
Pages (from-to)1935-1943
Number of pages9
JournalAmerican Journal of Pathology
Issue number7
Publication statusPublished - 2015

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  • EMC MM-02-41-04

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