Publication Date

2016

Document Type

Thesis

Committee Members

Nancy Bigley (Committee Member), Mauricio Di Fulvio (Committee Member), Barbara Hull (Committee Member), Courtney Sulentic (Advisor)

Degree Name

Master of Science (MS)

Abstract

The immunoglobulin heavy chain gene (Igh) is regulated by numerous regulatory elements including the 3'Igh regulatory region (3'IghRR). Several transcription factors are involved in modulating the 3'IghRR including NF-B, AP-1, and the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor that mediates the transcription of genes involved in the metabolism of environmental toxicants such as TCDD. TCDD binds AhR and regulates immunoglobulin (Ig) expression in B cells of animal models. This modulation appears to be directly mediated by binding of the AhR to dioxin response elements (DRE) within the 3'IghRR. Structural differences have been found between the human IGH and mouse Igh genes, including a duplication of the 3'IGHRR in humans and a polymorphic region in the human hs1.2 enhancer. This region is sensitive to TCCD-mediated modulation in mouse models whereas in in humans, several polymorphisms have been correlated with several autoimmune diseases. The objective of this study was to determine the transcriptional influence of human 3'IGHRR enhancer and sensitivity to TCDD. Using luciferase reporters controlled by the 3'IGHRR enhancers and cellular models including two well characterized B-cell lines: mouse CH12.LX and human CL-01. These cell lines can be induced to secrete Ig and can undergo class switch recombination. Our results suggest that, unlike mouse 3'IghRR, human 3'IGHRR is not sensitive to TCDD. Therefore, the role of this region remains to be determined.

Page Count

71

Department or Program

Microbiology and Immunology

Year Degree Awarded

2016

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