Tumor Necrosis Factor (TNF) is not Necessary for the Development of Severe Inflammatory Arthritis
TNF is a highly inflammatory protein that is overproduced in rheumatoid arthritis (RA) and is, therefore, thought to play a pivotal role in its pathogenesis. The impressive clinical response of RA patients to inhibitors of TNF, and the ability of genetically-induced overproduction of TNF to induce inflammatory arthritis in animals, have reinforced this concept. However, not all patients respond to inhibitors of TNF. This raises the possibility that inflammatory arthritis may not be absolutely dependent upon TNF.
To examine this question, Campbell et al (J. Clin. Invest. 107:1519-1527, 2001) examined a strain of mouse in which TNF was “knocked out” (Tnf-/-). Chronic inflammatory arthritis was induced by injection of collagen in Tnf-/- and wild type (WT) mice and compared. Tnf-/- mice had some reduction in the clinical parameters of arthritis and significantly more normal joints. However, severe disease was evident in 54% of arthritic Tnf-/- joints. Furthermore, acute arthritis was also successfully induced (by BSA/IL-1 injections) in Tnf-/- mice, although reduced in incidence and severity compared to WT mice.
There were several unexpected findings as well. Collagen-immunized Tnf-/- mice developed massive splenomegaly and lymphadenopathy associated with increased memory CD4+ T cells and activated lymph node B cells. In addition, collagen-immunized Tnf-/- mice had impaired Ig class switching, but preserved T cell proliferative responses to collagen and enhanced interferon-gamma production.
Editorial Comment: These interesting studies illustrate that TNF is important but not essential for the development of inflammatory arthritis. The data reinforce the complexity of mechanisms of inflammation in RA, and support continued efforts to identify more effective therapies. There has been concern that chronic TNF inhibition may be associated with increased incidence of infection. The defect in isotype class switching (from IgM to IgG) observed in the TNF deficient mice could play a role in increased susceptibility to infection. The significance of the increase in CD4+ memory cells, splenomegaly and lymphadenopathy in arthritic Tnf-/- mice remains to be determined.
