Severe inflammatory arthritis and lymphadenopathy in the absence of TNF
Ian K. Campbell, … , Kate E. Lawlor, Ian P. Wicks
Ian K. Campbell, … , Kate E. Lawlor, Ian P. Wicks
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1519-1527. https://doi.org/10.1172/JCI12724.
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Article

Severe inflammatory arthritis and lymphadenopathy in the absence of TNF

Abstract

It has been postulated that TNF has a pivotal role in a cytokine cascade that results in joint inflammation and destruction in rheumatoid arthritis (RA). To evaluate this, we examined the response of TNF-deficient (Tnf–/–) mice in two models of RA. Collagen-induced arthritis (CIA) was induced by injection of chick type II collagen (CII) in CFA. Tnf–/– mice had some reduction in the clinical parameters of CIA and, on histology, significantly more normal joints. However, severe disease was evident in 54% of arthritic Tnf–/– joints. Tnf–/– mice had impaired Ig class switching, but preserved T cell proliferative responses to CII and enhanced IFN-γ production. Interestingly, CII-immunized Tnf–/– mice developed lymphadenopathy and splenomegaly associated with increased memory CD4+ T cells and activated lymph node B cells. Acute inflammatory arthritis was also reduced in Tnf–/– mice, although again some mice exhibited severe disease. We conclude that TNF is important but not essential for inflammatory arthritis; in each model, severe arthritis could proceed even in the complete absence of TNF. These results call into doubt the concept that TNF is obligatory for chronic autoimmune and acute inflammatory arthritis and provide a rationale for further studies into TNF-independent cytokine pathways in arthritis.

Authors

Ian K. Campbell, Kristy O’Donnell, Kate E. Lawlor, Ian P. Wicks

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Figure 7

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Cytokine mRNA expression in synovial tissue from Tnf–/– and WT mice with...
Cytokine mRNA expression in synovial tissue from Tnf–/– and WT mice with acute inflammatory arthritis. Synovium (s) of acutely arthritic knee joints or adjacent muscle (m) was dissected from Tnf–/– (–/–) and WT (+/+) mice. Total RNA was extracted and cytokine mRNA levels assessed by RPA. (a) Synovial cytokine expression patterns were similar for Tnf–/– and WT mice. Tissue specificity is shown by the lack of cytokine expression in muscle. (b) Presence of TNF mRNA in WT but not in Tnf–/– synovial extracts. Each lane represents tissue pooled from five mice with L32 being a control for RNA loading. Data are representative of two experiments performed.