Peripheral apoptosis and limited clonal deletion during physiologic murine B lymphocyte development

Area of Science:

• Immunology
• Cell Biology
• Autoimmunity

Background:

• Self-reactive and polyreactive B cells must be eliminated during development to prevent autoimmunity.
• The role of apoptosis in B cell development and maintaining self-tolerance is not fully understood.

Purpose of the Study:

• To quantify self-reactivity, polyreactivity, and apoptosis during physiological B lymphocyte development.
• To elucidate the mechanisms of B cell tolerance and apoptosis in the bone marrow and periphery.

Main Methods:

• Quantification of B cell receptor self-reactivity and polyreactivity.
• Analysis of apoptosis in developing B cells.
• Cloning and characterization of B cell receptors from both viable and apoptotic B cells.

Main Results:

• Self-reactivity and polyreactivity are highest in early immature B cells and decrease during bone marrow maturation.
• Apoptosis occurs at low levels in the bone marrow, with apoptotic B cells showing similar self-reactivity to viable cells.
• Apoptosis increases significantly in transitional B cells exiting the bone marrow, but most are not self-reactive/polyreactive.
• Lack of survival signaling, rather than clonal deletion, drives most peripheral transitional B cell apoptosis.

Conclusions:

• Receptor editing likely eliminates the majority of self-reactive B cells in the bone marrow.
• Apoptosis-independent mechanisms are crucial for removing self-reactive B cells during bone marrow development.
• Peripheral B cell apoptosis is primarily mediated by insufficient survival signals, highlighting a distinct tolerance mechanism outside the bone marrow.