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Title: Why do vaccines fail the elderly?
Author: Martin, Victoria Georgina
ISNI:       0000 0004 7656 0370
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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Age results in the gradual deterioration and dysregulation of the immune system (Immunosenescence) and often results in an inability to fight infections and respond effectively to vaccines. The aim of this thesis was to investigate molecular and cellular defects that occur in B cells from the elderly, which might explain the inability of the elderly to respond to immunological challenges. We analysed the immunoglobulin (Ig) heavy chain repertoire of different B cell populations from the peripheral blood of young (18-45 years) and old (65+) donors using high throughput sequencing and found age-related alterations in IGHV, IGHD, IGHJ gene usage and in CDR3 characteristics. We saw that positive and negative selection pressures are dampened in the elderly, showing that aged donors are less able to refine their repertoire as effectively as the young. This change in selection may help explain the known age-related increase in antibody autoreactivity. We used mass cytometry and a panel of 30 markers to phenotype peripheral blood B cells from young and old donors more thoroughly and discovered that the IgD/CD27 defined B cell populations are not homogenous and contain further subpopulations, in particular of IgMhi and IgMlo cells. Therefore, our future repertoire analyses, and assumptions about repertoire selection, would need to take account of the variations in these populations. Finally, we undertook microarray analysis of peripheral blood naïve B cells from young and old donors, 8hrs after stimulation with both T-dependent (TD) and T-independent (TI) stimuli. We saw age-related differences, predominantly in unstimulated and TI stimulated cells, that could indicate changes in BCR signalling, class switching and susceptibility to apoptosis. Overall, we have interlinking observations, which together suggest two broad hypotheses. 1) Transitional and naive cells may have more autoreactive Ig gene repertoires as a result of apoptotic resistance in early B cell development, thereby contributing to the higher autoimmunity seen in the elderly. 2) In the elderly there may be dysregulation of signalling activation pathways upon TI stimulation. This in turn may result in the impaired generation of IgM memory cells, lowered AID expression and reduced class switching, skewing the IgM memory populations and therefore contributing to the diminished protection against TI antigens in the elderly. In conclusion, we have shown that ageing likely affects B cells in a number of ways, intrinsic signalling changes possibly contributing to changes in molecular and cellular repertoires.
Supervisor: Dunn-Walters, Deborah Kay ; John, Susan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available