Lessons from animal models of arthritis.
There is increasing thought that autoantibodies to systemic self-antigens may provide a principal effector mechanism for the initiation and propagation of joint inflammation. The recent identification of arthritis transfer with antibodies to the self-antigen glucose-6-phosphate isomerase has boosted this interest. Fc receptor involvement in arthritis has been evaluated, identifying pro-inflammatory and inhibitory Fc gamma receptor subtypes, and demonstrating a link between Fc gamma receptor expression, cytokine production, cartilage destruction, and mouse strain susceptibility to immune complex arthritis. Further proof of a key role of interleukin (IL)-1 in arthritis was provided by the occurrence of spontaneous arthritis in IL-1 receptor antagonist knockout mice and elicitation of full-blown arthritis in tumor necrosis factor (TNF)-deficient mice. IL-18 (part of the IL-1 family) is a crucial upstream cytokine that, with IL-12, induces IL-1 and TNF and promotes arthritis and T-cell differentiation. IL-18 neutralization improved arthritis outcome, but its central role in host defense against bacterial infections may complicate therapeutic IL-18 targeting. T helper 1 (Th1) cells may aggravate arthritis and joint destruction through the production of IL-17, which shows joint destructive potential independent of IL-1. Studies have also focused on the control of receptor activator of nuclear factor kappaB ligand, modulation with IL-4, and regulation of downstream mediators in tissue destruction. Gene therapeutic approaches proved efficacious and will provide future ways to control arthritis.
Van den Berg
Wim B
WB
Center of Rheumatology Research and Advanced Therapeutics, Nijmegen Center of Molecular Life Sciences, Geert Grooteplein 26-28, 6500 HB Nijmegen, The Netherlands. w.vandenberg@reuma.azn.nl
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000503:physiopathology* / Q000628:therapy; D001323:Autoantibodies / Q000502:physiology; D016207:Cytokines / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice
D001323:Autoantibodies; D016207:Cytokines