Date of Award

January 2024

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Inci Yildirim

Abstract

Background: Sickle Cell Disease (SCD) is the most common genetic hematological disorder and puts individuals at increased risk of morbidity and mortality due to infectious disease. Those with SCD also have a reduced capacity to mount successful vaccine responses compared to healthy individuals but there is an incomplete understanding of the mechanisms behind this.

Objectives: We aim to investigate the role of hemin as a potential contributor to inflammatory dysregulation and decreased vaccine immunogenicity in patients with SCD.

Methods: Peripheral blood mononuclear cells (PBMC) were isolated from patients with SCD aged 7-22 and healthy participants aged 22-30. We utilized flow cytometry to identify cytokine production by monocytes after stimulation with either hemin, hemoglobin S (HbS), or lipopolysaccharide (LPS). The percentages of monocytes positive for production of TNF-a, IL-1b, IL-6, IL-8, and MCP-1 were compared using Mann-Whitney tests with a significance cutoff value of p=0.05.

Results: Following a 6-hour incubation, at baseline there was an increase in activated monocytes producing IL-1b in patients with SCD compared to healthy controls (p=0.0047). With LPS stimulation there was no statistically significant difference between SCD patients and healthy controls. After stimulation with HbS, there was an increase in activated monocytes producing IL-1b in SCD patients compared to healthy controls (p=0.0032). After 6-hour stimulation with hemin, there was an increase in activated monocytes producing IL-1b (p=0.021) and TNF-a (p=0.00052) in SCD patients compared to healthy controls.

Conclusion: Overall, the data suggests that hemin is not a major contributor to the inflammatory response following 6-hour stimulation of PBMC. Future studies should work to further investigate other potential sources of inflammation and its role in vaccine immunogenicity for patients with SCD.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/07/2025

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