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Early life immune ontogeny in a vulnerable population

University of British Columbia

The first year of life represents a time of marked susceptibility to infections, particularly in resource-poor regions and regions where HIV is endemic, such as sub-Saharan Africa. Infants that are exposed to HIV are among the World’s most vulnerable to infectious morbidity and mortality. Immune defense mechanisms may differ between global regions with high rates of childhood death and disease. This dissertation examines innate immune development throughout the first year of life in HIV unexposed (UE) South African infants, and compares their immune development with HIV-exposed uninfected (HEU) South African infants. Clinical outcomes and adaptive immune responses to vaccination were also compared between HEU and UE infants. Specifically, infection incidence and severity were correlated with multidimensional assessments of immune profiles, including innate immune responses to pathogen-associated stimuli, as well as antibody responses to vaccination, all contrasting HEU and UE infants. I found that monocyte, classical dendritic cell and plasmacytoid dendritic cell responses in our cohort were mostly similar to responses measured in other global regions. However, responses to endotoxin matured more rapidly in South African infants. HEU mononuclear cells demonstrated enhanced pro-inflammatory responses when compared to UE, particularly during the first 6 weeks of life, and altered responses were specific to pathogen type. HEU vaccine responses were similar, but in some instances developed protective titers more rapidly than UE. Incidence of infection was equivalent between HEU and UE. However, HEU infants experienced more severe infections, and peak relative risk occurred within the first 12 months of life. This cohort study represents the first prospective, longitudinal description of immune ontogeny throughout the first year of life. My PhD dissertation provides a thorough examination of innate immune development during this time period. HEU are a population that suffers disproportionately from infectious disease, and our findings suggest HEU infants have altered immune defense mechanisms. This collection of work provides a foundation to mechanistically dissect etiological factors that predispose high-risk groups, such as HEU infants, to suffer increased infectious morbidity and mortality.

Text

2016-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/58210

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/