MIYASAKA Masayuki Osaka University Medical School, Professor, 医学部, 教授 (50064613)
UCHIYAMA Yasuo Osaka University Medical School, Professor, 医学部, 教授 (10049091)
NAGATA Shigekazu Osaka University Medical School, Professor, 医学部, 教授 (70114428)
TOMITA Tetsuya Osaka University Medical School, Assistant Professor, 医学部, 助手 (30283766)
|Budget Amount *help
¥13,900,000 (Direct Cost : ¥13,900,000)
Fiscal Year 1998 : ¥5,200,000 (Direct Cost : ¥5,200,000)
Fiscal Year 1997 : ¥8,700,000 (Direct Cost : ¥8,700,000)
Although most of all investigations on etiology of rheumatoid arthritis (RA) have been focusing on synovial tissue, its proliferation in affected joints of patients with severe RA is rather mild. Thus we thought that the main lesion of the disease might be elsewhere than synovium.
We found. In bone marrow of affected joints of severe RA patients, myeloid cells with abnormal cell surface antigens which originated from tile cells with apparently normal cell surface antigens in iliac bone marrow. The differentiation was accelerated by IL-1 beta and GM-CSF, and was obstructed by T cells.
Also observed was, in iliac bone marrow in mild RA patients, increase arid activation of lymphoid cells with elevated levels of IL-1 and IL-8. Furthermore, in culture of iliac bone marrow cells obtained from severe RA patients, enhancement of osteoclastogenesis was detected, suggesting osteoclasts are one of tile causes of general osteoporosis in severe RA.
Since these abnormal cells could not be maintained i
n normal culture conditions, we established stromal 'nurse cell' lines from bone marrow and synovium of severe RA patients. Nurse cells are characterized by 'pseudoemperipolesis', holding lymnphoid cells underneath, as well as their important roles in immune reaction, supporting lymphoid cells in differentiation, maturation, and apoptosis.
RA nurse cells produce IL-6, IL-8, G-CSF, GM-CSF and hyaluronan by themselves. Moreover, when co-cultured with lymphoid cells and observed manifesting pseudoemperipolesis, they produce not only proinflammatory cytokines such as IL-1 beta and TNF-alpha, but also matrix metalloproteinases and cathepsins which directly associate with joint destruction in RA. The down-regulation of apoptosis of these abnormal cells can be explained by enhancement of soluble Fas ligand which we observed in rheumatoid synovial fluid
It can he concluded that RA nurse cells, in the center of cellular network, form and maintain the pathogenesis of RA, and that they possibly associate with joint destruction by themselves. Less