Severe inflammatory arthritis and lymphadenopathy in the absence of TNF.
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-gamma 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.
Campbell
I K
IK
Reid Rheumatology Laboratory, Division of Autoimmunity and Transplantation, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
O'Donnell
K
K
Lawlor
K E
KE
Wicks
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IP
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003094:Collagen / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D007136:Immunoglobulins / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008206:Lymphatic Diseases / Q000209:etiology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D013163:Splenomegaly / Q000473:pathology; D013583:Synovial Membrane / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D007136:Immunoglobulins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen