2001 Fiscal Year Final Research Report Summary
Cellular mechanisms of tolerance breakdown in autoantibody production
| Project/Area Number |
11470089
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Keio University |
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Principal Investigator |
KOYASU Shigeo Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
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| Co-Investigator(Kenkyū-buntansha) |
MASAYUKI Amagai Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (90212563)
NISHIKAWA Takeji Keio University, School of Medicine, Professor, 医学部, 教授 (50051579)
OHTEKI Toshiaki Keio University, School of Medicine, Instructor, 医学部, 助手 (50233200)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Self tolerance / T cell / B cell / autoimmune disease / pemphigus / knockout mouse / Rag-2 |
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| Research Abstract |
It is believed that mechanisms leading self-tolerance are operative in both B and T cells although those for B cells are less clarified. Since production of antibodies by B cells generally requires T cell help, breakdown of self-tolerance in both B and T cell compartments is expected to take place. Alternatively, it is possible that self-reactive B cells are widely present in our body and breakdown of T cell tolerance is sufficient to trigger autoimmunity. However, experimental data supporting this notion have rarely been obtained. We have developed a new method to generate active autoimmune disease model by employing autoantigen knockout mice. In a given knockout mice self tolerance against the defective molecule is not acquired. Adoptive transfer of lymphocytes from such autoantigen knockout mice after immunization with antigens into antigen-positive mice should provide an active disease animal model for autoimmune diseases. We have applied this method to a well characterized autoimmune disease, pemphigus vulgaris (PV). It is well established in human PV that IgG antibodies against Dsg3, a cadherin type cell-to-cell adhesion molecule expressed in stratified squamous epithelia, play a pathogenic role to cause blisters in the skin and mucous membranes. Adoptive transfer of Dsg3^<-/-> splenocytes immunized with recombinant mouse Dsg3 to Rag2^<-/-> recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis. When purified T and B cells from Dsg3^<-/->, Dsg3^<+/-> or Dsg3^<+/+> mice were mixed with various combinations and transferred to Rag2^<-/-> mice, pathogenic anti-Dsg3 IgG production was observed only with a combination of Dsg3^<-/-> T and Dsg3^<-/-> B cells but not with the other combinations. These results suggest that loss of tolerance against Dsg3 in both B and T cells is important for the development of autoimmune state of PV.
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Research Products
(20 results)
