Date of Award

6-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbiology, Immunology, and Biochemistry

Research Advisor

Elizabeth A. Fitzpatrick, PhD

Committee

Weikuan Gu, PhD Kui Li, PhD Claire L. Simpson, PhD Robert W. Williams, PhD

Keywords

BXD mice; Hypersensitivity Pneumonotis, IVIG, Multiple Sclerosis, Th17 cells

Abstract

Hypersensitivity and autoimmune diseases are complex synergistic effect of environmental, genetic and other factors. T helper 17 (Th17) cells play a critical role in the immune pathology. Th17 cells are a group of specialized CD4+ T cells with potential pro-inflammatory function which are different from other T cells such as T helper 1 (Th1) cells or T helper 2 (Th2) cells. Th17 cell development and differentiation processes are strictly regulated through complex pathways. Th17 cells are characterized by secreting cytokines such as IL-17 and IL-22. Studies have shown that Th17 cells and IL-17 have been implicated in the pathogenesis of many hypersensitivity and autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Therefore, the study of Th17 cell differentiation and its regulatory mechanism will help with better understanding of the regulation of these diseases and may also potentially identify new targets for their treatment. In this study, we worked on two diseases: hypersensitivity pneumonitis (HP) and multiple sclerosis (MS). Both of them can be mediated by Th17 cells. HP is a hypersensitivity disease in the lung which may result in chronic lung fibrosis with high mortality. Corticosteroids such as prednisolone may help to control acute HP symptoms but may also produce side effects and not be effective to all patients. Because under the same environmental conditions not all exposed individuals get the diseases, the genetics may play an important role in HP. Our hypothesis is that severity and risk for developing HP will be most strongly influenced by genetic variants that are involved in regulation of the T cell response. Data from mouse inbred lines of BXD family were analyzed to identify the genes involved in susceptibility to HP and were used in the study of the mechanisms by which they contribute to the disease. We found that BXD strains exhibited variability in the T cell response to the development of HP and the expression level of Cdh2 was correlated with that of IL-17, which may contribute to inflammation in the lung and lung fibrosis. MS is an autoimmune disease occurring in the central nervous system (CNS) which may result in jeopardy of a patient’s lifespan. There is no cure for the disease, and the current treatment can only reduce the relapsing frequency and severity. Although the exact mechanism is unclear, one promising option is the use of high dose of intravenous immunoglobulin (IVIG). IVIG exhibits anti-inflammatory properties that are protective in autoimmune and inflammatory diseases. But it is still not the ideal treatment due to the large dosages and toxic effects. Gliknik lnc. developed fully recombinant IgG multimers as a therapeutic option for autoimmune diseases, called Stradomers. Our study found that the Stradomers could prevent the development of experimental autoimmune encephalitis (EAE), the mouse model of MS, with fewer Th17 cells infiltrated into the CNS. The therapeutic effect of Stradomers is dose-dependent and lower doses of Stradomers could delay the onset of EAE in our study. Overall, this dissertation addressed new feasible theoretical basis to prevent the development of HP and MS through Th17 pathways.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

http://orcid.org/0000-0003-2071-3326

DOI

10.21007/etd.cghs.2022.0595

Additional Files
2022-010-Wang-DOA.pdf (174 kB)
Declaration of Authorship
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