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<sup>+</sup> 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<sup>+</sup> ECs, (pre)FDCs, and ILC3s with respect to TLSs in RA ST. TLS<sup>+</sup> 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<sup>+</sup> tissues. In contrast, TLS<sup>+</sup> tissues contained significantly more NIK<sup>+</sup> ECs and perivascular platelet-derived growth factor receptor β<sup>+</sup> preFDCs, which correlated significantly with the quantity of FDCs. We established a strong link between NIK<sup>+</sup> ECs, (pre)FDCs, and the presence of TLSs, indicating that NIK<sup>+</sup> ECs may not only be important orchestrators of lymph node development but also contribute to the formation of TLSs in chronic inflammation.

doi.org/10.1016/j.ajpath.2015.03.012, hdl.handle.net/1765/81854
American Journal of Pathology
Department of Hematology

Noort, A.R, van Zoest, K.P.M, van Baarsen, L.G.M, Maracle, C.X, Helder, B, Papazian, N, … Tas, S.W. (2015). Tertiary Lymphoid Structures in Rheumatoid Arthritis: NF-κB-Inducing Kinase-Positive Endothelial Cells as Central Players. American Journal of Pathology, 185(7), 1935–1943. doi:10.1016/j.ajpath.2015.03.012