Master of Science
Pathology and Laboratory Medicine
T helper 2 (Th2) cells play a crucial role in type 2-high asthma. Glucocorticoids (GC) are the primary treatment for type 2-high asthma but their long-term impact on Th2 cells is unclear. Severe asthmatics receiving high-dose GC treatment still experience symptoms, which are associated with increased frequency of Th2-Th17 cells. We hypothesized that chronic GC treatment primes Th2 cells to transition to Th2-Th17 cells in the presence of Th17 differentiating cytokines (TGF-β/IL-21). Experiments revealed that Th2 cells can transition to Th2-Th17 cells that were more viable than Th2 cells in chronic GC. Th2-Th17 cells exposed to chronic GC produced less thioredoxin interacting protein (TXNIP) mRNA, an inhibitor of the antioxidant thioredoxin (TXN), and more ATP-binding cassette sub-family B member 1 (ABCB1) mRNA, a multi-drug resistance gene. These results indicate Th2-Th17 cells may be less susceptible to GC-induced apoptosis due to acquiring stronger antioxidant capacity and/or faster export of GC.
Summary for Lay Audience
Asthma affects about 262 million people around the world. There are several different types of asthma, the most common form being Type 2-high asthma which is characterized by T helper 2 (Th2) cells, type 2 inflammation, and good responsiveness to glucocorticoid (GC) therapy. Type 2-high severe asthmatics have increased levels of Th2 cells as well as a hybrid cell type called Th2-Th17 that are less responsive to GC therapy, even at higher doses. Stress during both childhood and adulthood is strongly linked with worse asthma and a mixed Th2-Th17 immune response. This may be due to increased levels of the stress hormone cortisol, also a GC, as it has been shown to enhance naïve T cell differentiation to Th17 cells. Based on this evidence, we hypothesized that chronic exposure to GCs, whether from asthma therapy or psychological stress, encourages Th2 cells to become Th2-Th17 cells. Our results reveal that by creating a Th17 conducive environment, Th2 cells indeed transition to Th2-Th17 cells. Moreover, Th2-Th17 cells were also more resistant than Th2 cells to GC-induced cell death, which may allow them to survive longer and be better able to mediate persistent asthma symptoms. Th17-inducing conditions arise in response to environmental exposures such as stress, infection, and air pollution and so our findings are expected to help further uncover how these environments contribute to asthma severity.
Al Jawhri, MohdWessam, "The Effects of Glucocorticoids on Th2 Cell Phenotype and Function" (2023). Electronic Thesis and Dissertation Repository. 9350.
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