Background Tumor necrosis factor (TNF) is a critical effector and a therapeutic target in rheumatoid arthritis (RA). TNF inhibitors are also preferably used in the treatment of severe autoimmune uveitis, however, previous reports showed that TNF inhibitors, in some cases, may worsen the comorbid uveitis in RA patients or trigger new onset of uveitis. Therefore, it is very important to know the precise role of TNF signaling in uveitis. TNF is mediated by two structurally related, but functionally distinct, receptors, p55 and p75. It has already been shown that genetic disruption of the TNF p55 receptor in mice has reduced the severity of experimental autoimmune uveitis (EAU), a preclinical model for uveitis. However, it remains unclear whether mice lacking p75 or mice lacking both p55 and p75 are also resistant to EAU.
Objectives To dissect the effect of TNF signaling through the TNF p55 or p75 receptor in the development of EAU.
Methods The p55-/-, p75-/-, and p55-/-p75-/- mice on a C57BL/6 background were generated by successive backcrossing to C57BL/6 for ten generations. EAU was initiated by immunization with interphotoreceptor retinoid binding protein (IRBP) in complete Freund's adjuvant and administration of pertussis toxin. Fundus examination was performed 10 to 28 days after immunization. The eyes were enucleated at the peak of EAU for histopathological evaluation. Severity of uveitis was assessed using clinical and histological scoring system of EAU.
Results The severity of EAU in mice lacking p55 was reduced compared to that in control WT mice, as described previously. In contrast, the severity of EAU in mice lacking p75 was not reduced compared to that in control WT mice both clinically and histopathologically. Mice lacking both p55 and p75 did not develop a typical acute disease but showed a slowly progressive form of EAU. Ocular inflammation reached its peak around day 16 post immunization in control WT mice, whereas, in mice lacking both p55 and p75, inflammation reached its peak around day 20 post immunization. Clinical and histopathological scores at the peak of EAU were not significantly different between control (1.83±0.88, 1.88±1.73) and mice lacking both p55 and p75. (1.72±1.33, 1.86±1.68)
Conclusions Unlike p55-/- mice, both p75-/- and p55-/-p75-/- mice retained susceptibility to EAU. The severities at the peak of EAU in these mice were not reduced compared to control WT mice, although p55-/-p75-/- mice exhibited low score uveitis in the early phase. Thus, EAU could be induced by TNF-independent pathway and this might be a potential mechanism in uveitis patients resistant to TNF inhibitors.
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Wendling D, Paccou J, Berthelot JM, Flipo RM, Guillaume-Czitrom S, Prati C, Dernis E, Direz G, Ferrazzi V, Ristori JM. New onset of uveitis during anti-tumor necrosis factor treatment for rheumatic diseases. Semin Arthritis Rheum. 2011;41:503-10.
Disclosure of Interest None declared
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