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Autoreactive B cells escape clonal deletion by expressing multiple antigen receptors
J J Kenny1, L J Rezanka, A Lustig
1Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. kennyj@grc.nia.nih.gov
Journal of Immunology (Baltimore, Md. : 1950)
|February 7, 2001
Summary
Autoreactive B cells can persist by diluting receptor expression, a mechanism crucial for fighting pathogens like Streptococcus pneumoniae. This discovery offers new insights into immune system regulation and potential therapeutic targets.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Autoreactive lymphocytes pose a significant challenge in immunology due to their potential for self-tissue damage.
- Phosphocholine (PC)-specific B cells expressing certain immunoglobulin (Ig) receptors often exhibit autoreactive properties.
- Understanding mechanisms that control or rescue autoreactive B cells is critical for immune homeostasis.
Purpose of the Study:
- To investigate the behavior of autoreactive phosphocholine (PC)-specific B cells in a genetically modified mouse model.
- To explore novel mechanisms by which autoreactive B cells can escape functional anergy and persist.
- To determine if rescuing autoreactive B cells has beneficial implications for host defense against pathogens.
Main Methods:
- Generation of recombinase-activating gene (Rag-2-/-) knockout mice with IgH and L chain transgenes encoding a PC-specific Ig receptor.
- Introduction of a second IgL chain into mice already expressing the autoreactive PC-specific Ig receptor.
- Analysis of B cell development, function, and antibody secretion in genetically modified mice.
- Assessment of B cell anergy and rescue mechanisms, including the role of bcl-2 and allelic exclusion.
Main Results:
- PC-specific B cells in Rag-2-/- mice showed developmental arrest, inability to secrete antibodies, and escape from clonal deletion, developing into B1 B cells.
- Overexpression of bcl-2 rescued these autoreactive B cells.
- Dual L chain expression in Rag-2-/- mice led to B cells coexpressing anti-PC and other antibodies.
- Coexpression of additional Ig molecules rescued autoreactive anti-PC B cells, relieving anergy and enabling circulating anti-PC-Abs.
Conclusions:
- A novel mechanism termed 'receptor dilution' via compromised allelic exclusion allows autoreactive B cells to persist.
- Rescue of autoreactive B cells is demonstrated, suggesting a potential benefit for host defense.
- These findings highlight the complex regulation of B cell tolerance and the potential protective role of certain autoreactive antibodies against pathogens like Streptococcus pneumoniae.