UBC Theses and Dissertations
Corticosteroid-Binding Globulin (CBG) : deficiencies and the role of CBG in disease processes Hill, Lesley Ann
Corticosteroid-binding globulin (CBG, SERPINA6) is a serine protease inhibitor family member produced by hepatocytes. Plasma CBG transports biologically active glucocorticoids, determines their bioavailability to target tissues and acts as an acute-phase negative protein with a role in the delivery of glucocorticoids to sites of inflammation. A few CBG-deficient individuals have been identified, yet the clinical significance of this remain unclear. In this thesis, I investigated 1) the biochemical consequences of naturally occurring single nucleotide polymorphisms in the SERPINA6 gene, 2) the role of human CBG during infections and acute inflammation and 3) CBG as a biomarker of inflammation in rats. A comprehensive analysis of functionally relevant naturally occurring SERPINA6 SNP revealed 11 CBG variants with abnormal production and/or function, diminished responses to proteolytic cleavage of the CBG reactive center loop (RCL) or altered recognition by monoclonal antibodies. In a genome-wide association study, plasma cortisol levels were most closely associated with SERPINA6 SNPs and plasma CBG-cortisol binding capacity. These studies indicate that human CBG variants need to be considered in clinical evaluations of patients with abnormal cortisol levels. In addition, I obtained evidence that discrepancies in CBG values obtained by the 9G12 ELISA compared to CBG binding capacity and 12G2 ELISA are likely due to differential N-glycosylation rather than proteolysis, as recently reported. In relation to human inflammation, the bacterial protease Pseudomonas aeruginosa elastase was shown to cleave the RCL and α-2-macroglobulin specifically inhibited this. ICU patients with a variety of illnesses had significantly reduced plasma CBG levels, with the lowest levels in individuals with severe inflammation. Similar results were observed in a rodent model of inflammation, where significant reductions in plasma CBG levels were associated with CBG proteolysis and the down-regulation of hepatic Serpina6 expression. In addition, lower baseline plasma CBG levels in Harlan Sprague Dawley rats were linked with an increased susceptibility to inflammation. Together, the human and rodent studies highlight the importance of CBG in inflammatory reactions and suggest that CBG is a useful biomarker of inflammation onset and severity.
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