2001 Fiscal Year Final Research Report Summary
Basic studies for development of disease-specific therapeutic strategies against autoimmune diseases
| Project/Area Number |
12470181
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Dermatology
|
|---|
| Research Institution | Keio University |
|---|
Principal Investigator |
NISHIKAWA Takeji Keio University School of Medicine, Professor, 医学部, 教授 (50051579)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ISHIKO Akira Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (10202988)
AMAGAI Masayuki Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (90212563)
TANAKA Masaru Keio University School of Medicine, Associate Professor, 医学部, 助教授 (40188339)
ANZAI Hidemi Keio University School of Medicine, Lecturer, 医学部, 助手 (90276345)
OHYAMA Manabu Keio University School of Medicine, Lecturer, 医学部, 助手 (10255424)
|
|---|
| Project Period (FY) |
2000 – 2001
|
| Keywords | Autoimmune / Autoantibody / Model mouse / epitope / bullous disease / knockout mouse / pemphigus / desmoglein |
|---|
| Research Abstract |
The purpose of this study is to obtain basic knowledge for the development of disease-specific therapeutic strategies against autoimmune diseases. We used pemphigus, an autoimmune blistering diseases of the skin and mucous membranes. Patients with pemphigus vulgaris (PV) and foliaceus (PF) have circulating pathogenic IgG autoantibody against desmoglein. 3 (Dsg3) and desmoglein 1 (Dsg 1), respectively. We took two independent approaches, one was using patients specimen and the other was using a mouse model of pemphigus vulgaris. In the approach using patients specimen, we generated Dsg1- and Dsg3-domain-swapped molecules and point-mutated Dsg3 molecules with Dsg 1-specific residues by baculovirus expression to map conformational epitopes of Dsg 1 and Dsg3 in PF and PV. The binding of autoantibodies to the mutant molecules was assessed by competition ELISA. Domain-swapped molecules containing the N-terminal 161 residues of Dsg1 and Dsg3 yielded greater than 50% competition in 30/43 (69.8%) PF sera and 31/40 (77.5%) PV sera, respectively. Within these N-terminal regions, most of the epitopes were mapped to residues 26-87 of Dsg1 and 25-88 of Dsg3. These findings suggest that the dominant autoimmune epitopes in both PF and PV are found in the N-terminal adhesive surfaces of Dsgs. In the approach using the PV mouse model, we succeeded in obtaining several anti-Dsg3 mouse monoclonal IgG antibodies from the PV model mice. Among them AK19 and AK23 showed the pathogenic activity in inducing blister formation. At this point we could not obtain any specific peptides to bind these pathogenic antibodies. Through these studies we could obtain important tools to develop the disease-specific immune suppressive therapy.
|
