Petra Aradi1,2, Zalán Horváth1,2, Éva Kemecsei1,2, László Bálint1,2 and Zoltán Jakus1,2
1 Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
2 MTA-SE „Lendület” Lymphatic Physiology Research Group, Budapest, Hungary
Introduction: Rheumatoid arthritis is the most common, systemic autoimmune disease, which is characterized by chronic inflammation of the synovial joints often resulting in progressive joint destruction and disability. The tight cooperation between the immune system and the lymphatic system is well documented in antimicrobial functions but the possible role of lymphatics in the development of autoimmune inflammatory diseases remains unclear.
Aim: Our aim was to characterize the role of lymphatics in autoimmune arthritis with genetic methods.
Methods: In our studies Flt4kd/+ mice carrying a germline point mutant kinase dead Vegfr3 allele were used. Autoimmune arthritis was induced in the K/BxN serum-transfer arthritis model, and the disease progression was followed by the measurement of ankle thickness and assessment of clinical score. The ankles were also processed for paraffin-based histology followed by HE and immunostaining against lymphatic and immune cell markers.
Results: In our experiments we found the complete lack of lymphatics in the skin including the ear and joint area of Flt4kd/+ mice, while the lymphatic structures were present in the internal organs (small intestine and lung). We characterized the development of the autoimmune arthritis in Flt4+/+ and Flt4kd/+ animals in the K/BxN serum-transfer arthritis model, the inflammation was reduced in Flt4kd/+ mice. Autoimmune arthritis induction resulted in dynamically changing lymphatic morphology and unexpectedly induced lymphatic growth in Flt4kd/+ animals with dilated lymphatic vessels.
Conclusion: Our results revealed that dynamic changes of lymphatic morphology occur in autoimmune arthritis, and the inflammation is reduced in the Flt4kd/+ mice lacking lymphatics in the joint area. They also suggest that distinct mechanisms regulate the developmental and inflammatory lymphangiogenic program. Our findings define novel aspects of the interactions between the immune system and lymphatic structures which may stimulate the development of novel therapeutic approaches in the future for the treatment of autoimmune diseases.
Doctoral School: Doctoral School of Molecular Medicine
Program: Cellular and Molecular Physiology
Supervisor: Dr. Zoltán Jakus
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