Background and Objectives Tertiary lymphoid structures (TLS) can be observed in rheumatoid arthritis (RA) synovial tissue, and often contain high endothelial venules (HEV) and follicular dendritic cells (FDC). Endothelial cell (EC)-specific lymphotoxin (LT)β receptor signalling is critical for lymph node and HEV formation and FDC arise from PDGFRβ+ perivascular precursor cells that require lymphoid tissue inducer (LTi) cells and LTβ for their expansion. RA synovial tissue contains EC expressing NF-κB inducing kinase (NIK) which is pivotal in LTβ-induced non-canonical NF-κB signalling. Therefore, we studied the presence and relation between NIK+ EC, (pre)FDC and group 3 innate lymphoid cells (ILC3) that comprise LTi cells with TLS in RA synovial tissue.
Materials and Methods Microarray data were used to explore the expression levels of genes involved in NF-κB signalling in RA synovial tissue + /- TLS. Expression of NIK, PNAd, FDC-M1, RORc, and PDGFRβ was evaluated in tissues containing TLS (n = 25) and tissues without TLS (n = 15) using immunofluorescence microscopy.
Results RA synovial tissues with TLS contained a significantly higher expression of non-canonical NF-κB related genes, including NIK. This was confirmed by immunohistochemistry: NIK was highly expressed in PNAd+ HEV. Interestingly, we could detect small numbers of ILC3 in RA synovial tissue, which did not clearly correlate with the presence of TLS. In contrast, tissues with TLS contained significantly more perivascular PDGFRβ+ cells correlating significantly with the amount of FDC.
Conclusion We established a strong correlation between NIK+ EC, perivascular (pre)FDC and TLS. Furthermore, we demonstrate for the first time that ILC3 are present in human RA synovial tissue, but only in very low numbers and without a clear correlation with TLS. Therefore, NIK+ EC and perivascular (pre)FDC may be more important as orchestrators of TLS.