# NIH grant: Human Anti-Carbohydrate repertoire stability and dynamics throughout life (1R01AI195802-01A1) — retained record

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NIH grant 1R01AI195802-01A1: Human Anti-Carbohydrate repertoire stability and dynamics throughout life
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: John Franklin Kearney. Award: $480853.
Start: 2026-08-01T00:00:00.
Project Summary
Human humoral immunity is mediated by individual B cells endowed with unique antigen receptors. Following
antigen engagement, these cells undergo clonal expansion and differentiation into antibody secreting cells (ASC)
and memory B cells (Bmem). During immune responses, B cells undergo somatic hypermutation which changes
the genes encoding their antigen receptors, a process that when coupled with selection within germinal centers
(GC) improves the quality of their B cell antigen receptors (BCR), typically resulting in higher affinity. Following
most productive immune responses, expanded clones undergo a contraction phase reducing their numbers.
Within the T cell compartment, chronic antigen exposure to antigen maintains increased frequency of clones,
resulting in oligoclonality and a reduction of antigen receptor diversity within the global repertoire. Oligoclonal
expansions have been observed in the B cell compartment of older adults as well, however the mechanisms
responsible for this effect are not known. Serum antibodies reactive with a wide array of carbohydrate
determinants are present in all humans, as are B cells reactive with these carbohydrate structures. In contrast
to commonly evaluated B cell specificities that encompass antigens encountered intermittently throughout an
individual's lifetime, anti-carbohydrate (AC) responses are driven by glycan determinants derived from the
commensal microbiota. Accordingly, these antigens are never `cleared' and are continuously available for
immune activation. The effect of this chronic antigen exposure on the AC B cell repertoire is not known. As ACAs
are the products of B cells that undergo immune activation including GC involvement, somatic mutation, affinity
maturation, and differentiation, we hypothesize the AC-repertoire is subjected to recurrent selection promoting
the activation and expansion of only a few clones, thereby becoming increasingly oligoclonal in aged adults. The
proposal is focused on evaluating the repertoire, Ab binding properties, and the auto-reactive and anti-microbial
potential of the AC repertoire directed at the two most frequently targeted carbohydrates in healthy humans
across 6 decades of the human life span. We are using state-of-the-art antigen-specific B cell isolation, BCR
sequencing, cloning, and expression to evaluate the diversity and binding properties of the human AC repertoire.
We are combining these technologies with high-dimensional cytometric antigen arrays, serum Ab fractionation,
functional Ab, and transcriptomic assays to determine changes that occur within the ACA-repertoire across the
human lifespan. Our efforts to elucidate the effects of chronic antigen exposure of microbial antigens on the
human B cell immune system will illuminate mechanisms causing age-associated loss of B cell repertoire
diversity and accompanying immunosenescence.
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