Theses and Dissertations

ORCID

0009-0003-6685-0358

Advisor

Kaplan, Barbara

Committee Member

Ross, Matthew

Committee Member

Pharr, Gregory

Committee Member

Carr, Russell

Date of Degree

8-12-2026

Original embargo terms

Visible MSU Only 1 year

Document Type

Dissertation - Campus Access Only

Major

Environmental Toxicology

Degree Name

Doctor of Philosophy (Ph.D.)

College

College of Veterinary Medicine

Department

Department of Comparative Biomedical Sciences

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor known to regulate immune responses and exert immunosuppressive effects. While previous studies have established that AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses antibody production in the experimental autoimmune encephalomyelitis (EAE) model of Multiple Sclerosis (MS), it remains unclear whether the suppression of antibody translates into altered antibody-mediated signaling. Therefore, this study aimed to investigate the impact of AHR ligand-mediated modulation of antibody production and on antibody-triggered Fcγ receptor (FcγR)-mediated immune responses in innate cells. Our data established that TCDD robustly suppressed IgG1, IgG2a and IgG2b antibody production in EAE mice, whereas indole-3-carbinol (I3C) exhibited inconsistent and variable suppressive effects. Despite that, both TCDD and I3C consistently reduced the expression of proinflammatory genes Il6, Tnf, oxidative stress associated gene Noxo1, and FcγR genes in the cerebellum of the disease mice. To assess antibody-triggered signaling in vitro, we developed and optimized in vitro IgG1 immune complex systems by combining streptavidin with biotinylated IgG1. This immune complex stimulated FcγR activation by increasing the release of IL-6 and TNF-α and cytokine secretion,C3a complement protein release, and increased CD86 marker expression on F4/80+ macrophages. Using the same approach, we also developed an IgG2a and IgG2b-based stimulation model for splenocytes (SPLC), RAW 264.7 macrophages, and BV2 microglia cells, although IgG2a only stimulated BV2 cells. With these immune complex tools, we demonstrated that IgG2b-mediated downstream signaling is more sensitive to AHR ligands than IgG1 in SPLC and RAW cells. Among the tested AHR ligands, I3C consistently attenuated IgG2b-induced cytokine production in innate cells through early inhibition of Akt phosphorylation. In addition, our findings from human peripheral blood mononuclear cells (PBMCs) revealed that TCDD significantly suppressed IgG1 antibody production stimulated by pokeweed mitogen (PWM) and IgG1/IgG2 immune complex-triggered IL-6 cytokine production. Although I3C had limited and donor-specific effects on antibody production in human PBMCs, it suppressed antibodytriggered signaling. Collectively, our data suggests that AHR-ligand mediated suppression of antibody production leads to suppression of FcγR activating signaling in target cells. This indicates FcγR signaling could be a critical target for developing immunomodulatory therapeutics for autoimmune diseases.

Sponsorship (Optional)

NIH R15 ES027650

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