The impact of ERAP1 functions on innate and adaptive immunity in human disease models
Blake, Maja Kristin K.
author
Amalfitano, Andrea
thesis advisor
Dorrance, Anne
degree committee member
Liby, Karen
degree committee member
Rockwell, Cheryl
degree committee member
Goudreau, John
degree committee member
text
Text
Theses
No place, unknown, or undetermined
2022
2022
eng
English
application/pdf
208 pages
ERAP1 has long been appreciated for its role in antigen presentation during the adaptive immune response. It is a peptidase in the endoplasmic reticulum that trims peptide antigens prior to their loading onto awaiting MHC-1. However, ERAP1 has also been shown to play an important role in innate immune responses, although the mechanisms underlying these associations have been unclear. The ERAP1 gene has also been linked to a number of autoimmune diseases including, but not limited to Multiple Sclerosis, Ankylosing Spondylitis, and Ulcerative Colitis. In addition, it is known to be altered in various tumor types as a means of immune evasion, and inhibitors for ERAP1 have shown promising results against tumors in vitro. Therefore, ERAP1's significance in the susceptibility to diverse diseases is vast, and further study into how this protein participates in both innate and adaptive immune response mechanisms is justified. Our lab has previously published that immune cells and animals deficient in ERAP1 display proinflammatory phenotypes. In this dissertation, the mechanism as to how disruptions in normal ERAP1 function leads to proinflammatory phenotypes is studied. First, proinflammatory mechanisms within a critical innate immune cell, macrophages, are discerned using both ex vivo models and an in vivo inducible colitis mouse model. ERAP1 deficiency in the setting of a murine model of autoimmunity is also evaluated, revealing both disturbances in B cell development and function as dependent on normal ERAP1 activity, and that these disturbances can lead to exaggerated neuroinflammation in several murine models of MS. ERAP1 dependent proinflammatory mechanisms within B cells are further studied ex vivo using global RNA sequencing technology along with flow cytometry-based methods. Together, the results of these studies reveal that loss of ERAP1 function causes enhanced ER stress within the cell, leading to UPR activation, increased inflammasome activity, and evidence of increased pyroptosis. Given the broad spectrum of ERAP1 functions on immune cell functions, we capitalized on these insights to determine how ERAP1 inhibition might impact diseases such as cancer. Specifically, our results confirmed that that ERAP1 inhibition promoted NK cell directed tumor killing, a modality that had never been attempted until now. In conclusion, this dissertation capitalizes upon insights gained from human genetic studies associating ERAP1 with a variety of human disease susceptibilities, identifying the molecular mechanisms underlying these associations, and also illuminates possible new therapies for human diseases derived from study of ERAP1.
Maja Kristin K. Blake
Thesis (Ph. D.)--Michigan State University. Pharmacology and Toxicology, 2022
Includes bibliographical references
Immunology
Autoimmune diseases
Endoplasmic reticulum
Immunology
Immunology
Autoimmune diseases
Endoplasmic reticulum
Electronic Theses & Dissertations
etd
9798351463407
on1373601352
1373601352
29394780
Blake_grad.msu_0128D_19445
In Copyright
https://doi.org/doi:10.25335/gryy-7312
aacr
MiEM
Michigan State University. Libraries
2023-08-08
2024-03-02
in00006796007
Converted from MSUL MARC and ProQuest DISSXML to MODS version 3.7 using a custom XSLT.
eng