International Immunology Advance Access originally published online on September 2, 2008
International Immunology 2008 20(10):1351-1360; doi:10.1093/intimm/dxn095
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Autoreactive B-cell elimination by pathogenic IgG specific for the same antigen: implications for peripheral tolerance
1 Department of Dermatology
2 Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
3 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
4 Present address: Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA
Correspondence to: M. Amagai; E-mail: amagai{at}sc.itc.keio.ac.jp
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.
Keywords: autoimmunity, B cells, Fas, skin
Transmitting editor: T. Kurosaki
Received 2 April 2008, accepted 21 July 2008.