title: Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis.
abstract: Heparanase is an endo-glucuronidase that degrades heparan sulfate chains. The enzyme is expressed at a low level in normal organs; however, elevated expression of heparanase has been detected in several inflammatory conditions, e.g. in the synovial joints of rheumatoid arthritis (RA) patients. Herein, we have applied the model of collagen-induced arthritis (CIA) to transgenic mice overexpressing human heparanase (Hpa-tg) along with wildtype (WT) mice. About 50% of the induced animals developed clinical symptoms, i.e. swelling of joints, and there were no differences between the Hpa-tg and WT mice in the incidence of disease. However, Hpa-tg mice displayed an earlier response and developed more severe symptoms. Examination of cells from thymus, spleen and lymph nodes revealed increased innate and adaptive immune responses of the Hpa-tg mice, reflected by increased proportions of macrophages, antigen presenting cells and plasmacytoid dendritic cells as well as Helios-positive CD4+and CD8+T cells. Furthermore, splenic lymphocytes from Hpa-tg mice showed higher proliferation activity. Our results suggest that elevated expression of heparanase augmented both the innate and adaptive immune system and propagated inflammatory reactions in the murine RA model.
authors.affiliation: Department of Medical Biochemistry and Microbiology, University of Uppsala, The Biomedical Center, Box 582, SE-751 23 Uppsala, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Digre
authors.affiliation: Department of Medical Cell Biology, Uppsala University, The Biomedical Center, Box 571, SE-751 23 Uppsala, Sweden.
authors.forename: Kailash
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Biomedical Sciences and Veterinary Public Health, Section of Immunology, Swedish University of Agricultural Sciences, VHC, Box 7028, SE-75007 Uppsala, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Åbrink
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Reijmers
authors.affiliation: Department of Medical Cell Biology, Uppsala University, The Biomedical Center, Box 571, SE-751 23 Uppsala, Sweden.
authors.forename: Stellan
authors.initials: S
authors.lastname: Sandler
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Medical Biochemistry and Microbiology, University of Uppsala, The Biomedical Center, Box 582, SE-751 23 Uppsala, Sweden.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000276:immunology*; D002645:Chickens; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000378:metabolism*; D007113:Immunity, Innate; D007249:Inflammation / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D018655:Lymphocyte Count; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D000099175:Heparanase
chemical_list: D015703:Antigens, CD; D005966:Glucuronidase; D007371:Interferon-gamma; D020381:Interleukin-17; D000099175:Heparanase