| Research Abstract |
It is still unclear what functional molecules are critical for the development of intractable inflammatory diseases including collagen disease, although several parameters of autoimmunity have been pointed out in these diseases. This project was performed to identify high molecular proteins responsible for the development of collagen disease and to analyze their gene expression by using a murine model, MRL/Mp-lpr/lpr (MRL/lpr) mice. This strain of mice spontaneously develops a lethal glomerulonephritis, arteritis and arthritis, associated with the expression of the immunological disorder-inducing gene, lpr, which is recently clarified to be Fas antigen deletion mutant. These mice develop all of these diseases in the same individual, but MRL genetic background is required for them in addition to the lpr gene.
We clarified that the background genes for these diseases are able to be genetically segregated each other by using the MRL hybrid mice with non-autoimmune-prone mice. Considering t
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he facts from these MRL hybrid mice, we identified the responsible proteins for collagen disease in MRL/lpr mice; IgG3 subclass for glomerulonephritis and TNF for granulomatous arteritis.
In further analyses of IgG3, we succeeded in obtaining nephritogenic IgG3 producing clones against normal or SCID mice, and moreover these clone generated regular variations of lupus nephritis in histopathological manifestations. Immunoglobulin gene analysis of these clones clarified that each nephritogenic IgG3 is derived from a different B cell precursor and used a different VH germline gene. Moreover, one of these IgG3 was not associated with somatic mutation in the VH region, indicating that somatic mutation in the VH region is not required for the development of nephritogenic antibody. Furthermore, this germline VH gene was identical to that found in a non-autoimmune-prone mice. Thus, there may be no autoimmune-prone specific al- lelism in the germline VH gene relevant to the nephritogenic antibody.
Regarding TNF on the development of arteritis, there is no RFLP of TNF-exon 4 among MRL and non- autoimmune-prone mice. However, it was clear that the individuals with arteritis among the MRL hybrid mice manifest a positive correlation between TNF and IL-1 beta mRNA level, but not between other macrophage-related cytokine mRNA such as LIF, M-CSF and Eta-1. This fact indicates that particular potential of macrophages are required for the development of arteritis in MRL/lpr mice, restricted with their background genes.
Further studies of the sequences in the variable regions of IgG3 responsible for the nephritogenicity, including the association of the constant regions, and the induction mechanisms of nephritogenic antibody- producing B cell clones are required. An arteritis-prone strain of mice established from the MRL hybrid mice will be useful for further studies of the genetic basis of arteritis and of the responsible genes. Less
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