|Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1989: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1988: ¥5,600,000 (Direct Cost: ¥5,600,000)
In 1987, we identified a cell growth inhibitor, Iymphocyte blastogenesis inhibitory factor (LBIF) in the culture supernatant of a human histiocytic lymphoma, U937. In this study, we have attempted to clarify the molecular structure and function of LBIF. Results are summarized below.
1. It has been shown that LBIF is an arginine deiminase (EC 22.214.171.124) originated from Mycoplasma arginine, infecting U937 cells.
2. The nucleotide sequence of full-length cDNA clone encoding LBIF has been determined.
In a next series of functional analyses of LBIF, we have examined the effects of LBIF on the antibody production of autoimmune MRL mice in vitro.
3. It was demonstrated that the IgG antibody production was not inhibited by LBIF in spite of strong inhibition of IgA and IgM antibody production. These results were confirmed by culturing B cells in arginine-free medium supplemented with varying doses of urea cycle metabolities.
4. Thus, we demonstrated that gamma-committed B lymphocytes (B gamma) of MRL
mice selectively expressed the highly elevated Lーarginine syntyhesis while mu or alpha-committed B lymphocyted showed the normal level.
5. Normal murine lymphocytes are hardly able to utilize Lーcitrulline to grow and numal lymphocytes are not able to use Lーcitrulline at all.
Important implication of our findings are as follows and this abnormality sufficiently explain four important questions of systemic autoimmune disease, such as, (1), predominant propagation of gamma^+ cells, (2), predominant IgG production, (3), disease progression with aging and (4), drastic effects of dietary restriction on the disease manifestation.
Autoimmune diseases so far, tend to be considered on the basis of clonal selection (tolerance) or cytokine-responsiveness. This study strongly suggests that systemic autoimmune diseases should be reevaluated as metabolic disorders occurred in lymphocytes, whereas organ-specific autoimmune diseases may belong to immunological disorders with the abnormality of clonal selection. Thus, this study presents a novel perspective on the molecular mechanism of systemic autoimmune disease. Less