| Abstract | Harmful pathogenic IgG auto-antibodies are produced against desmoglein 3 (Dsg3) in pemphigus vulgaris, an autoimmune blistering disease. Dsg3 is a cadherin-type cell adhesion molecule expressed in desmosomes of the skin and mucous membranes. In AK7-transgenic mice expressing non-pathogenic AK7 IgM against Dsg3, autoreactive transgenic B cells escape from the deletion or inactivation and exist in the periphery. However, when a pathogenic anti-Dsg3 IgG1 mAb (AK23) capable of inducing blisters was injected into AK7-transgenic mice, AK7 B cells were eliminated from the bone marrow (BM) and spleen only when Dsg3 was expressed in the periphery. In contrast, non-pathogenic IgG mAbs (AK7, AK9) failed to eliminate AK7 B cells. Interestingly, the AK23-mediated elimination of mature AK7 B cells in the spleen was significantly diminished in AK7-transgenic mice on a Rag2(-/-) background while BM B cells were still eliminated, suggesting the presence of T-cell-dependent and -independent mechanisms. T cell transfer studies into AK7-Rag2(-/-) mice revealed that autoreactive B-cell elimination in the periphery requires CD4(+) T cells from wild-type mice but not from gld (FasL mutant) mice. The B-cell elimination was impaired in both BM and periphery when Bcl2 was over-expressed in AK7 B cells. These findings suggest that autoreactive B cells exist unless they are harmful, but once harmful or dangerous events such as tissue destruction are sensed, the mature autoreactive B cells in the periphery are eliminated via a Fas-mediated process in a CD4(+) T cell-dependent manner. |
| Authors | Takayuki Ota, Miyo Aoki-Ota, Kazuyuki Tsunoda, Takeji Nishikawa, Shigeo Koyasu, Masayuki Amagai
(Affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo160-8582, Japan)
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| Journal | International immunology
(Int Immunol)
Vol. 20
Issue 10
Pg. 1351-60
(Oct 2008)
ISSN: 1460-2377 England |
| PMID | 18765425
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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| Chemical References |
- Antigens, CD95
- Autoantigens
- Desmoglein 3
- Epitopes
- Fas protein, mouse
- Immunoglobulin G
- Immunoglobulin M
|
| Topics |
- Adoptive Transfer
- Animals
- Antigens, CD95
(immunology)
- Autoantigens
(immunology)
- Autoimmunity
(immunology)
- B-Lymphocytes
(immunology, metabolism)
- Cytotoxicity, Immunologic
(immunology)
- Desmoglein 3
(immunology)
- Epitopes
(blood, immunology)
- Immune Tolerance
- Immunoglobulin Class Switching
(immunology)
- Immunoglobulin G
(blood, immunology, metabolism)
- Immunoglobulin M
(blood, immunology, metabolism)
- Mice
- Mice, Transgenic
- Pemphigus
(blood, immunology)
- Signal Transduction
(immunology)
|
