title: 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.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ae R
authors.initials: AR
authors.lastname: Noort
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Katinka P M
authors.initials: KP
authors.lastname: van Zoest
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: van Baarsen
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Chrissta X
authors.initials: CX
authors.lastname: Maracle
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Boy
authors.initials: B
authors.lastname: Helder
authors.affiliation: Department of Hematology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Natalie
authors.initials: N
authors.lastname: Papazian
authors.affiliation: Department of Hematology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Romera-Hernandez
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Department of Hematology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Cupedo
authors.affiliation: Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: s.w.tas@amc.uva.nl.
authors.forename: Sander W
authors.initials: SW
authors.lastname: Tas
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C505697:LTBR protein, human