Background/Purpose: Tumor necrosis factor (TNF) is a critical effector of the autoimmune inflammation in rheumatoid arthritis (RA) and uveitis. TNF inhibitors are preferably used in the treatment of these autoimmune diseases. However, TNF inhibitors are not always effective in treating RA. Moreover, previous reports showed that some TNF inhibitors may even accelerate comorbid uveitis in RA patients. Therefore, it is very important to know the precise role of TNF signaling in RA and uveitis. TNF signals are mediated by two structurally related, but functionally distinct, receptors, p55 (TNFR1) and p75 (TNFR2). It has already been shown that genetic disruption of the TNF p55 receptor in mice can reduce the severity of collagen-induced arthritis (CIA) and experimental autoimmune uveitis (EAU), murine models of autoimmune arthritis and uveitis, respectively. However, it remains unclear whether mice lacking p75 or mice lacking both p55 and p75 are also resistant to CIA and EAU. In this study, we aimed to dissect the role of TNF signaling through the TNF p55 or p75 receptor in the development of EAU and CIA.

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 (CFA) and administration of pertussis toxin. CIA was induced by immunizing these mice with type II collagen in CFA twice. Clinical examination was performed and severities of EAU and CIA were assessed using clinical scoring system.

Results: In EAU, the severity in p55-/- mice was reduced compared to that in control WT mice, as described previously. In contrast, EAU in p75-/- mice was similar to, or slightly more severe than that in WT mice. Mice lacking both p55 and p75 did not develop a typical acute disease but exhibited delayed-onset uveitis. In CIA, p55-/- mice were protected from arthritis. In contrast, the severity of CIA in p75-/- mice tended to be increased compared to that in control WT mice. Mice lacking both p55 and p75 developed less severe arthritis than WT mice.

Conclusion: Unlike p55-/- mice, p75-/- mice retained susceptibility to CIA and EAU. TNF signaling through p75 might contribute to limit inflammation in CIA and EAU. Antagonists selective to p55 may be advantageous for the treatment of autoimmune arthritis and uveitis.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/collagen-induced-arthritis-and-uveitis-in-mice-lacking-tnf-receptors/