Date of Award
Doctor of Philosophy (PhD)
Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by itchy, red, scaly rashes. In the United States alone, AD affects 6-10% of the population and costs $5.3 billion dollars annually in medical treatment. The main pathogenic factors in AD appear to be impaired skin barrier function and inflammation. Specifically, AD-associated inflammation is driven by a type 2 inflammatory module involving T helper type 2 cells, group 2 innate lymphoid cells, and the type 2 cytokines. Therapeutic approaches currently focus directly on barrier restoration and immunosuppression. However, whether some aspect of the immune system might be impaired or required to regulate the aberrant inflammatory response observed in AD is less clear. AD patients do have an enhanced susceptibility to exacerbations of viral skin infections such eczema herpeticum and molluscum contagiosum, though the mechanisms underlying this susceptibility have yet to be fully defined. We demonstrate that AD patients harbor a deficiency in blood natural killer (NK) cells, key cellular mediators of antiviral immunity. Low numbers of blood NK cells have both diagnostic value for AD and improved along with clinical parameters and biomarkers in response to therapy. Over the past decade, NK cells have emerged as a complex and heterogeneous population characterized by a diverse repertoire of receptors and functional capacities. We therefore undertook multidimensional mass cytometry analysis and RNA profiling of blood NK cells, which revealed aberrant activation and susceptibility to cell death that was associated with a loss of mature NK cells from AD patients. Taken together, these findings indicate that NK cell reduction is a central feature of AD that may serve as a diagnostic and treatment-responsive biomarker. In addition to antiviral immunity, we hypothesized that NK cells may provide important inhibitory signals that are lost in the setting of AD-associated inflammation. Previous studies have indicated that NK cells and NK cell-derived cytokines can limit type 2 inflammation in other systems. In agreement with this, we found that NK cell deficiency in a murine model of AD was associated with enhanced type 2 inflammation in the skin, suggesting that NK cells play a critical immunoregulatory role. Based on these findings, we tested an NK cell-boosting cytokine superagonist as an immunotherapy treatment and found marked improvement in AD-like disease in mice. These findings implicate a systemic NK cell reduction in AD pathology and reveal a new treatment paradigm in which NK cells can be enhanced in order to restrain pathogenic type 2 inflammation and improve disease.
Chair and Committee
Brian S. Kim
Maxim Artyomov, Marco Colonna, Todd A. Fehniger, Eugene M. Oltz,
Mack, Madison R., "The Role of Natural Killer Cells in Atopic Dermatitis" (2019). Arts & Sciences Electronic Theses and Dissertations. 1925.
Available for download on Tuesday, August 15, 2119