Studies of TNF-alpha in Alpha-One Antitrypsin Deficient and healthy subjects

Gane, Jennie Margaret (2017). Studies of TNF-alpha in Alpha-One Antitrypsin Deficient and healthy subjects. University of Birmingham. Ph.D.

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Abstract

TNF-α, a pro-inflammatory cytokine, is implicated in the immune response in chronic obstructive pulmonary disease (COPD) secondary to Alpha-One Antitrypsin Deficiency (A1ATD). This thesis firstly describes studies in monocytes from A1ATD-related COPD subjects, examining the effect of the rs361525 TNF-A single nucleotide polymorphism, previously associated with 100-fold greater TNF-α concentration in the sputum of affected patients. Secondly, the autocrine effects of TNF-α on monocytes from healthy subjects are considered, in particular the differential roles of its two receptors, TNF-α receptor 1 (TNFR1) and 2 (TNFR2), an important topic given recent interest in selective TNFR1 blockade in TNF-α associated diseases.
Unexpectedly, TNF-α mRNA expression and secreted protein was not greater in A1ATD-related COPD subjects with the rs361525 polymorphism when compared to matched wild-type subjects. Reasons may include the cell type and stimulus used or inadequate power. In monocytes from healthy subjects, autocrine binding of TNF-α increased production of pro-and anti-inflammatory cytokines. Trends were observed for TNFR1 blockade to reduce both types of cytokine, for IL-10 to be reduced by TNFR2 blockade and for TNFR1 expression at the monocyte surface to be up-regulated by TNF-α-TNFR2 binding. Further studies are required to fully characterise the relative roles of TNFR1 and TNFR2 in monocytes.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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