International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Abe K 1, Wagner S 1, Kalaydjiev S 2, Jakob T 3, Franz TJ 2, Busch DH 2, Soewarto D 1, Fuchs H 1, Hrabé de Angelis M 1

1 Institute of Experimental Genetics, GSF National Research Center, Neuherberg, Germany, 2 Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany, 3 Division of Environmental Dermatology and Allergy, GSF National Research Center/Technical University Munich, Munich, Germany

Rheumatoid arthritis (RA) is a common human systemic autoimmune disease that leads to erosive destruction of diarthrodial joints.  Despite world-wide efforts, its etiology and pathogenesis are still incompletely understood.  Because of complex genetic background and environmental effects in humans, experimental animal models have the potential to accelerate dissection of molecular mechanisms leading to inflammatory arthritis.  From the Munich large scale ENU-mutagenesis screen, we have isolated a dominant mutation, Abnormal limb (Ali)18, that shows redness and swelling on the hind paws at adult stage.  Ali18 homozygous animals display very severe inflammation in the front and hind paws and tail: arthritis, dermatitis, vasculitis, and swelling. First, to elucidate how the immune system is involved in this systemic inflammation, we analyzed various immunological parameters by means of ELISA and flow cytometry. Although increased granulocyte populations and elevated levels of IgE were detected in peripheral blood of Ali18 homozygous mice, autoimmune markers such as rheumatoid factor and anti-DNA antibodies were  moderately upregulated. In lymph nodes and spleen of Ali18, increased populations of activated T lymphocytes (CD4+CD25+) were detected. Next, we used disease transfer systems to address what cell types contribute to the phenotypes. Bone marrow cells (BMCs) were injected intravenously to irradiated wild type animals. In contrast to control experiments using BMCs from wild type mice, BMCs from Ali18 mice could transfer the arthritis phenotypes. However, plasma from Ali18 mice failed to transfer the phenotypes. These results indicate that bone marrow derived cells, not  serum factors, play an important role in the inflammatory process. In addition, the dual energy x-ray absorptiometry radiograph (DEXA)  analysis showed a significant lower bone mineral density at the whole body of the Ali18 homozygous mice (p<0.0001). Bone marrow derived cells contribute to bone remodelling, although it is uncertain whether BMCs of Ali18 mice influence this phenotype directly or indirectly through inflammation. In patients with RA, generalised bone loss frequently occurs. Therefore, detailed analysis of bone loss in Ali18 mice provides an insight into mechanisms how systemic inflammation affects bone metabolism. The possible association of the Ali18 phenotypes in rheumatoid arthritis and/or seronegative

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