Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Antibody (Ab) response is crucial for adaptive immunity.
• Aged individuals, especially males, exhibit diminished Ab responses compared to younger individuals.
• The underlying molecular mechanisms, including B cell somatic hypermutation (SHM), are not fully understood.

Purpose of the Study:

• To investigate the effects of aging and sex on B cell SHM targeting and DNA repair activities.
• To identify molecular factors contributing to age-related differences in Ab response.

Main Methods:

• Analysis of B cell Ig repertoire sequences from 27 healthy human subjects (aged 20-89).
• Studied mutation patterns across 985,069 mutations from 123,415 sequences.
• Examined DNA repair gene expression in relation to age and sex.

Main Results:

• SHM mutability hierarchies were largely consistent across age and sex groups.
• Older males showed reduced mutations involving Phase II SHM DNA repair activities compared to younger males and females.
• Decreased expression of DNA mismatch repair genes involved in SHM was observed in older individuals, with greater reduction in males.

Conclusions:

• The somatic hypermutation (SHM) process is altered in some older individuals, particularly males.
• Age- and sex-specific alterations in DNA repair pathways impact Ig diversification.
• Findings provide insights into clinical differences in immunologic responses across age and sex groups.