Autoreactive B-cell elimination by pathogenic IgG specific for the same antigen: implications for peripheral tolerance.

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
• Journal: International immunology (Int Immunol) Vol. 20 Issue 10 Pg. 1351-60 (Oct 2008) ISSN: 1460-2377 [Electronic] England
• PMID: 18765425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantigens
• Desmoglein 3
• Epitopes
• Fas protein, mouse
• Immunoglobulin G
• Immunoglobulin M
• fas Receptor

Topics

• Adoptive Transfer
• Animals
• 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)
• fas Receptor (immunology)