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Title: Detection of subtle immune defects in individuals at risk of pneumococcal disease
Author: Asani, Furaha Florence
ISNI:       0000 0004 6500 3990
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Immunocompromised individuals are at increased risk of developing invasive pneumococcal disease (IPD). We have previously shown that IPD sufferers have defective in vitro B-cell responses to a T-independent antigen mimic (αδdex), relative to healthy controls. We hypothesized that similar defects will be found in HIV-infected individuals, who continue to be at greater risk of IPD despite antiretroviral therapy, and in Monoclonal Gammopathy of Undetermined Significance (MGUS) patients. Lymphocytes enriched from whole blood were cultured with addex alone and combined with anti-CD3, to assess both direct T- and B-cell effects, and T-cell help to B-cells. T- and B-cell activation and proliferation were assessed using standardised flow cytometry. B-cell subsets were stratified by CD19, CD10, CD20, CD21 and CD27 into plasmablasts, activated memory cells, resting memory cells, naive, and tissue-like memory cells. Results from 16 HIV-infected individuals [mean CD4 count 677.63/mm3, undetectable viral loads] showed no change in overall CD19+ B-cell activation but increased proliferation upon T-cell-helped pneumococcal-stimulation, compared to age-, sex- and ethnicity-matched controls. However, addex elicited significantly higher (p = 0.05) activation in plasmablasts in HIV-infected individuals compared to healthy controls. Furthermore, MGUS patients expressed significantly lower CD25 on CD8+ T-cells compared to healthy controls, following stimulation with anti-CD3 and anti-CD28 (p = 0.01). Age, sex and ethnicity were also found to influence T- and B-cell responses to polyclonal-stimulation in healthy individuals. Although activation of CD19+ B-cells was similar between HIV-infected adults and healthy controls, polyclonal B-cell stimulation reveals a persisting hyperactivation defect in the plasmablast B-cell compartment in HIV infection despite virological suppression. The findings in this study may indicate impaired immune control of pathogens such as S. pneumoniae in immunocompromised individuals.
Supervisor: de Silva, Thushan ; Heath, Andy ; Dockrell, David ; Marriott, Helen ; Foster, Rachel ; Snowden, John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available