Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Nuclear Factor-B Inducing Kinase Is Preferentially Expressed in Rheumatoid Arthritis Synovial Tissue Containing Ectopic Lymphoid Neogenesis.

Noort2,  Ae-Ri, van Zoest3,  Katinka P. M., Modesti4,  Mariagrazia, Tas2,  Sander W., Tak1,  Paul P.

Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
Academic Medical Center/University of Amsterdam, The Netherlands
Academic Medical Center/University of Amsterdam
University of Rome

Background:

Approximately 30% of synovial tissues derived from rheumatoid arthritis (RA) patients is characterized by ectopic lymphoid neogenesis (ELN). This results in structures that may resemble germinal centers, containing dendritic cells and aggregates of B and T cells. This process also occurs in other chronic inflammatory diseases. Nuclear factor-kB (NF-kB) transcription factors are essential for the expression of pro-inflammatory cytokines, but can also induce regulatory pathways. These regulatory circuits are thought to be modulated by the non-canonical NF-kB pathway of which NF-kB-inducing kinase (NIK) is a key mediator. Non-canonical NF-kB signaling can be triggered by stimuli like CD40L and lymphotoxin that are abundantly present in ELN. Therefore, the non-canonical NF-kB pathway might play an important role in ELN.

Objectives:

To investigate the expression and distribution of NIK in RA synovial tissue (ST) in relation to ELN and to study the functional role of non-canonical NF-kB signaling.

Methods:

ST was obtained via mini-arthroscopy from inflamed knee or ankle joints of RA patients with active disease. RA ST samples were analyzed by microarray analysis. Next, we evaluated the expression of NIK in ST of 40 RA patients using immunohistochemistry. NIK expression was scored on a semiquantitative 5-point scale (0–4) by 2 independent observers. Furthermore, we analyzed NIK and von Willebrand Factor (vWF) expression using immunofluorescence microscopy, not only in RA ST, but also in Grawitz tumour tissue and breast cancer tissue.

Results:

Microarray analysis showed increased relative expression of non-canonical NF-kB pathway associated genes in ST containing ELN compared to tissue samples without ELN (p<0.05). Next, we confirmed these findings by immunohistochemistry. ELN was present in 15 out of 40 RA ST. NIK expression was significantly higher in ST with ELN and more abundantly present within lymphocyte aggregates (1.53±0.32 vs 0.62±0.19; p<0.05). Of interest, in the tissue away from the lymphocyte aggregates, NIK was expressed by vascular structures. Further analysis revealed that NIK positive cells were negative for the lymphatic vessel markers LYVE-1 and podoplanin. Immunofluorescence microscopy demonstrated that NIK co-localised with the endothelial cell marker vWF. We observed co-expression of NIK and vWF not only in RA ST, but also in Grawitz tumor and breast cancer tissue. Functional studies on the role of non-canonical NF-kB signaling in endothelial cells are currently being performed.

Conclusion:

NIK is preferentially expressed in RA ST containing ectopic lymphoid aggregates. NIK expression in RA ST co-localised with vWF, indicating that NIK is expressed by blood vessel endothelial cells. These findings point towards an important role of the non-canonical NF-kB pathway in either blood vessel formation or in the activation of endothelial cells to attract immune cells. This could be exploited for the development of future new therapies, which would not only be applicable for RA but also for other diseases.

Acknowledgement:

SWT was supported by a VENI grant from the Netherlands Organisation for Scientific Research.

To cite this abstract, please use the following information:
Noort, Ae-Ri, van Zoest, Katinka P. M., Modesti, Mariagrazia, Tas, Sander W., Tak, Paul P.; Nuclear Factor-B Inducing Kinase Is Preferentially Expressed in Rheumatoid Arthritis Synovial Tissue Containing Ectopic Lymphoid Neogenesis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1416
DOI: 10.1002/art.29182

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