The size, composition, and dynamics of B cell subsets change with age, indicating shifts B cell homeostasis and selection. BLyS and its receptors play a central role in B cell homeostasis. Consequently, we hypothesize that BLyS mediated homeostatic processes are perturbed in aged individuals, leading to alterations in the dynamic and selective events that shape and maintain peripheral B cell pools. These studies will probe the relationship between BLyS-mediated homeostatic processes and age-associated changes among B cells.
In aim 1, we will determine whether age-associated shifts in B cell subsets and repertoire selection rely on BLyS-BR3 mediated processes. Marrow and splenic.B lineage subsets of A/WySnJ and A/J mice at various ages will be characterized for representation, magnitude and turnover rate. In addition, repertoire diversity of immature, transitional, follicular, and MZ subsets will be assessed in A/J and A/WySnJ mice at various ages. These studies will employ limiting dilution and fine specificity analyses of the influenza hemagglutinin (HA)-specific response, as well as CDR3 length analyses.
In aim 2, we will determine whether the lengthened lifespan of mature B cells in aged mice reflects enhanced ability to capture BLyS-BR3 signals. The levels of BLyS binding and BLyS receptor expression, as well as downstream mediators of BLyS and APRIL signaling, be followed as individuals age. We will establish whether these shifts reflect selection versus an intrinsic property of developing B cells in aged mice through analysis of reciprocal bone marrow chimeras. We will determine whether aged B cells enjoy a competitive advantage over young B cells in adoptive transfer, and whether this is abrogated by exogenous SLyS administration.
In aim 3, we will determine whether the age-associated appearance of serum autoantibodies relies on BLyS mediated events. The experiments in this aim will also use the A/WsnJ and A/J strains for comparison. Age-associated appearance of ANAs will be followed, the B lineage subsets responsible for ANA antibody formation will be identified, and the repertoires of ANA producing clonotypes assessed. In addition, we will directly test whether transitional selection against autoreactive specificities changes with age through cloning and analysis of expressed VLVH pairs.
In aims 1 -3, we will determine whether shifts in kinetics, selection and/or BLyS receptor expression in aged B cell populations reflect downstream outcomes of reduced EBP output, with Dr. Allman.
In aim 4, we will determine whether manipulation of BLyS levels can restore robust B and T cell responses following immunization. We will examine the immune response to influenza HA in aged and young individuals to determine whether pretreatment with BLyS or BLyS receptor agonists restore litres of HA-specific antibody, as well as elevated HA-specific T cell, and B cell frequencies following immunization.
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