Self-tolerance curtails the B cell repertoire to microbial epitopes

Area of Science:

• Immunology
• Autoimmunity
• B cell biology

Background:

• Immunological tolerance eliminates self-reactive B cells, including those recognizing cross-reactive foreign antigens.
• The impact of tolerance on the B cell repertoire against foreign antigens is not fully understood.
• Microbial pathogens can exploit B cell repertoire 'holes' by mimicking host antigens.

Purpose of the Study:

• To determine the repertoires of human B cell antigen receptors (BCRs) before and after the second B cell tolerance checkpoint.
• To compare B cell reactivity in healthy donors versus patients with systemic lupus erythematosus (SLE).
• To investigate the role of immune tolerance in shaping the B cell repertoire against foreign antigens.

Main Methods:

• Single-cell cultures were used to analyze B cell antigen receptor (BCR) repertoires.
• Transitional B cells (pre-tolerance) and mature B cells (post-tolerance) were analyzed.
• BCR reactivity was assessed in healthy donors and SLE patients.

Main Results:

• In healthy donors, ~70% of transitional B cells recognizing foreign antigens also bind self-antigens (foreign+self).
• Peripheral tolerance reduces the frequency of foreign+self-reactive mature B cells by half in healthy individuals.
• In SLE patients with defective tolerance, foreign+self-reactive B cell frequencies remain unchanged during B cell maturation.

Conclusions:

• Immune tolerance significantly reduces the scope of the BCR repertoire against microbial pathogens.
• Cross-reactivity between foreign and self-epitopes is more common than previously thought.
• Defective tolerance checkpoints in SLE lead to persistent foreign+self-reactive B cells.