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.
| Original language | English |
|---|---|
| Pages (from-to) | 1351-1360 |
| Number of pages | 10 |
| Journal | International Immunology |
| Volume | 20 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2008 |
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Keywords
- Autoimmunity
- B cells
- Fas
- Skin
ASJC Scopus subject areas
- Immunology
Cite this
Autoreactive B-cell elimination by pathogenic IgG specific for the same antigen : Implications for peripheral tolerance. / Ota, Takayuki; Aoki-ota, Miyo; Tsunoda, Kazuyuki; Nishikawa, Takeji; Koyasu, Shigeo; Amagai, Masayuki.
In: International Immunology, Vol. 20, No. 10, 2008, p. 1351-1360.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Autoreactive B-cell elimination by pathogenic IgG specific for the same antigen
T2 - Implications for peripheral tolerance
AU - Ota, Takayuki
AU - Aoki-ota, Miyo
AU - Tsunoda, Kazuyuki
AU - Nishikawa, Takeji
AU - Koyasu, Shigeo
AU - Amagai, Masayuki
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - B cells
KW - Fas
KW - Skin
UR - http://www.scopus.com/inward/record.url?scp=52949149409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52949149409&partnerID=8YFLogxK
U2 - 10.1093/intimm/dxn095
DO - 10.1093/intimm/dxn095
M3 - Article
C2 - 18765425
AN - SCOPUS:52949149409
VL - 20
SP - 1351
EP - 1360
JO - International Immunology
JF - International Immunology
SN - 0953-8178
IS - 10
ER -