Self-reactive VH4-34-expressing IgG B cells recognize commensal bacteria

Area of Science:

• Immunology
• Molecular Biology
• Microbiology

Background:

• The immunoglobulin (Ig) variable heavy chain 4-34 (VH4-34) gene segment encodes self-reactive antibodies recognizing erythrocyte I/i carbohydrates.
• VH4-34 clones are prevalent in naive B cells but scarce in healthy IgG memory B cells.

Purpose of the Study:

• To investigate the role of Toll-like receptor (TLR) signaling in regulating VH4-34 B cell populations and antibody self-reactivity.
• To understand the implications of VH4-34 antibody self-reactivity in the context of commensal bacteria interactions.

Main Methods:

• Analysis of B cell repertoires in healthy individuals and patients with genetic deficiencies in IRAK4 or MYD88 (TLR signaling components).
• Assessment of VH4-34 expressing B cell frequencies, somatic hypermutation, and antibody binding to I/i carbohydrates and bacterial antigens.

Main Results:

• Patients deficient in IRAK4 or MYD88 showed increased VH4-34 expressing IgG+ B cells with reduced somatic hypermutation.
• VH4-34 encoded IgGs from deficient patients retained I/i antigen recognition due to unmutated framework region 1 (FWR1), unlike healthy counterparts.
• This self-reactivity in VH4-34 antibodies correlated with binding to commensal bacteria antigens.

Conclusions:

• IRAK4 and MYD88 signaling are critical for eliminating or modifying self-reactive VH4-34 B cells.
• Germline-encoded self-reactive VH4-34 antibodies may function as an innate-like B cell population for containing commensal bacteria upon gut barrier breach.