Date of Award
Doctor of Philosophy (PhD)
The mammalian immune system is composed of innate and adaptive compartments, which cooperate with each other to maintain homeostasis and protect the host from the invasion by a variety of pathogens. The tight control of immune responses is extremely important for all individuals. Here, we discovered that the transcription factor basic helix-loop-helix family, member e40 (Bhlhe40) is a critical protein that regulates the autoimmune ("against self") and anti-microbial ("against non-self") responses of myeloid cells and T lymphocytes. Multiple sclerosis (MS) is a human neuroinflammatory disease in the central nervous system with an autoimmune etiology. We have reported that Bhlhe40 positively regulates the production of the pro-inflammatory cytokine, GM-CSF, but negatively regulates the production of the anti-inflammatory cytokine, IL-10, by CD4+ T cells. The absence of Bhlhe40 abrogates T cell pathogenicity and thus Bhlhe40-/- mice were resistant to the animal model of MS. Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is one of the most serious infectious diseases in the world. We have demonstrated that Bhlhe40 suppresses IL-10 expression by myeloid cells and T cells to ensure protective immunity to Mtb. Bhlhe40-deficient immune cells produce high levels of IL-10 which dampens the immune responses to Mtb infection and therefore renders Bhlhe40-/- mice highly susceptible to this pathogen. Our findings have uncovered the critical roles of Bhlhe40 in regulating inflammation during an autoimmune disorder and an infectious disease. Bhlhe40, or pathways that regulate its expression or function, might represent therapeutic targets for researchers to manipulate immune responses in human autoimmunity and infection.
Chair and Committee
Brian T. Edelson
Paul M. Allen, John H. Russell, Takeshi Egawa, Emil R. Unanue,
Lin, Chih-Chung, "The Role of Bhlhe40 in Autoimmune Neuroinflammation and Mycobacterial Infection" (2017). Arts & Sciences Electronic Theses and Dissertations. 1125.