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Dependence on interferon-gamma for the spontaneous occurrence of arthritis in DBA/1 mice
Patrick Matthys1, Rik J Lories, Bert De Klerck
1University of Leuven, Leuven, Belgium. Patrick.Matthys@rega.kuleuven.ac.be
Objective:
Male DBA/1 mice are known to spontaneously develop arthritis in the hind legs. The present study was undertaken to investigate the role of endogenous interferon-gamma (IFNgamma) in the pathogenesis of this ankylosing enthesopathy.
Methods:
The role of IFNgamma was studied by examining the development of arthritis in IFNgamma receptor-knockout (IFNgammaR-KO) DBA/1 mice as compared with wild-type mice, and by treatment of wild-type mice with monoclonal anti-IFNgamma antibody. IFNgamma-disrupted and wild-type mice were mixed and housed in the same cage, and clinical symptoms of arthritis were assessed weekly for at least 9 weeks. Histologic examination was performed at the end of the experiment.
Results:
In DBA/1 wild-type mice, 70% of the animals developed clinical symptoms of spontaneous arthritis, such as redness and swelling of the proximal interphalangeal joints, toe stiffness, and ankylosis. As evident from microscopic evaluation, the arthritis was mainly characterized by formation of new cartilage and bone, originating at the entheses and leading to ankylosis. The incidence and severity of arthritis, both clinically and histologically, were significantly reduced in IFNgammaR-KO mice. In wild-type mice, neutralizing anti-IFNgamma antibody inhibited the occurrence of the disease for the duration of treatment.
Conclusion:
The results suggest that endogenous IFNgamma plays an important role in the initial stages of spontaneous arthritis, and that the inflammatory components in its pathogenesis are more prominent than has been believed. In view of the similarity between this disease and spondylarthropathies in humans, the data suggest that endogenous IFNgamma may also play a disease-promoting role in the human condition and thus may serve as a target for therapy.
Insights
Endogenous interferon-gamma (IFNgamma) drives spontaneous arthritis in male DBA/1 mice. Blocking IFNgamma significantly reduced disease incidence and severity, suggesting it as a therapeutic target for related human conditions.
Area of Science:
- Immunology
- Rheumatology
- Animal Models of Disease
Background:
- Male DBA/1 mice spontaneously develop hind leg arthritis, a condition known as ankylosing enthesopathy.
- The role of endogenous interferon-gamma (IFNgamma) in the pathogenesis of this spontaneous arthritis remains to be fully elucidated.
Purpose of the Study:
- To investigate the specific role of endogenous IFNgamma in the development of spontaneous arthritis in male DBA/1 mice.
- To determine if IFNgamma contributes to the pathogenesis of ankylosing enthesopathy in this animal model.
Main Methods:
- Compared arthritis development in IFNgamma receptor-knockout (IFNgammaR-KO) DBA/1 mice with wild-type littermates.
- Administered monoclonal anti-IFNgamma antibody to wild-type DBA/1 mice to neutralize endogenous IFNgamma.
- Assessed clinical and histological signs of arthritis weekly for at least 9 weeks in co-housed mice.
Main Results:
- 70% of wild-type DBA/1 mice developed spontaneous arthritis, characterized by joint swelling, stiffness, and ankylosis.
- Arthritis in wild-type mice involved new cartilage and bone formation at entheses, leading to ankylosis.
- IFNgammaR-KO mice exhibited significantly reduced incidence and severity of arthritis, both clinically and histologically.
- Neutralizing anti-IFNgamma antibody treatment inhibited arthritis development in wild-type mice during the treatment period.
Conclusions:
- Endogenous IFNgamma plays a critical role in the early stages of spontaneous arthritis in male DBA/1 mice.
- The inflammatory processes in this arthritis model are significantly influenced by IFNgamma.
- Given the similarity to human spondylarthropathies, endogenous IFNgamma may be a therapeutic target for related human diseases.
