Human IGH variants predict antibody dysregulation by environmental AhR ligands

About This Grant

SUMMARY Antibody production in B lymphocytes is essential for survival because antibodies (IgM, IgG, IgA) provide host immunity against bacterial and viral infections. Even mild to moderate reductions in antibody levels can lead to increased infections and higher rates of morbidity and mortality. Environmental toxicants, such as dioxin-like chemicals that act through the aryl hydrocarbon receptor (AhR) have been shown to inhibit Ig heavy chain (Igh) expression, antibody secretion, and resistance to infections. The AhR is a nuclear transcription factor that not only acts as a sensor for environmental stress, but also plays an important regulatory role in numerous biological processes. We discovered that a ~40 kb transcriptional regulatory region within the mouse Igh gene, the 3¢IghRR, is a molecular target of the AhR. The 3¢IghRR is essential for antibody production. In contrast to the mouse, the human antibody gene is unique, not only structurally due to gene duplication but also because the human 3¢IGHRR is polymorphic. This questions whether mouse studies evaluating the Igh gene translate to the ~288 kb human IGH gene, representing a significant gap in our understanding of human antibody production and therefore the susceptibility of humans to environmental stressors and toxicants. To address this gap in knowledge, we have created human B-lymphocyte cell lines to test the hypothesis that polymorphisms in the 3¢IGHRR control human antibody production and sensitivity to AhR ligands by regulating genomic interactions within the IGH gene. The proposed studies are novel and relevant because they directly evaluate the transcriptional control of a large and essential gene in the production of antibodies and will determine how host genetics and environmental stressors/toxicants that bind the AhR influence antibody production. The following specific aims will be addressed: 1) Define the role of 3¢IGHRR variants on molecular processes (i.e., IGH expression, antibody secretion, class switch recombination) of antibody production in response to AhR ligands; 2) Determine the mechanism (canonical vs. noncanonical) of AhR effects on antibody production in the context of the 3¢IGHRR variants; 3) Define genomic interactions within the 3¢IGHRR variants induced during antibody production and AhR modulation. Utilization of genetically modified B- lymphocyte cellular models and primary human B lymphocytes will define the adverse outcome pathway of AhR-mediated susceptibility and the genetic regulation of human antibody production. Linking AhR and transcriptional interactions with specific functional effects will lead to rational drug design in controlling antibody-mediated disease states.