Glycan-Reactive Innate-like B Cells and Developmental Checkpoints

Area of Science:

• Immunology
• B cell biology
• Autoimmunity

Background:

• B-1 B cells play a role in natural antibody production.
• Self-antigens can influence B cell development and tolerance.
• N-acetyl-d-glucosamine (GlcNAc) is a self-antigen expressed on various cells and molecules.

Purpose of the Study:

• To investigate the role of self-antigens, specifically GlcNAc, in the development of GlcNAc-reactive B-1 B cells.
• To understand how self-antigen exposure affects B cell maturation, selection, and function.

Main Methods:

• Development of transgenic mice (VHHGAC39 TG) expressing an Ig H chain specific for GlcNAc.
• Analysis of B cell development stages in transgenic mice.
• Competitive mixed bone marrow chimeras.
• Immunization studies.
• Transfer of B cells into RAG-/- mice.
• In vivo treatment with GlcNAc-specific monoclonal antibodies (mAbs).

Main Results:

• GlcNAc-reactive B-1 B cell development was normal during ontogeny but arrested at the transitional-2 stage in adult TG mice.
• Impaired allelic exclusion and accumulation of B cells coexpressing endogenous Ig gene rearrangements were observed.
• VHHGAC39 B cell fitness was reduced in competitive chimeras.
• Despite developmental blocks, immunized TG mice produced anti-GlcNAc Abs, and transferred B cells showed expansion and antibody production.
• Chronic GlcNAc antigen masking in young TG mice led to decreased GlcNAc-binding B cells but increased B1-a cells.
• BCR H chain editing promoted endogenous allele expression, aiding escape from anergy/deletion.

Conclusions:

• GlcNAc-reactive B cell development is sensitive to the availability of autologous GlcNAc antigens.
• Self-antigen access can impede the maturation of newly formed GlcNAc-reactive B cells.
• BCR editing provides a mechanism for potentially self-reactive B cells to escape deletion.