Dissertation
The role of type I interferon signaling in early dacryoadenitis in the nonobese diabetic mouse model of Sjögren’s disease
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007487
Abstract
Sjögren’s Disease is a debilitating autoimmune disease of the lacrimal and salivary glands. As disease progresses, immune cells infiltrate and aggregate in the glands resulting in destruction of the tissue. Nonobese diabetic (NOD) mice spontaneously develop salivary and lacrimal gland autoimmunity with histopathology similar to human disease. Previous work has demonstrated that disruption of the type I interferon (IFN) signaling pathway protects NOD mice from developing lacrimal gland disease. To better understand the role of type I IFN signaling on lacrimal gland disease, I utilized whole tissue RNA sequencing data from the lacrimal gland of wild-type and IFNAR1 KO NOD mice. I determined that many innate and adaptive immune pathways are upregulated downstream of type I IFN signaling including cytokine-cytokine receptor interaction, chemokine signaling and antigen processing and presentation.
While these data demonstrated that both innate and adaptive pathways are impacted by type I IFN signaling, it was not known which immune subsets express the IFNAR1 receptor in early lacrimal gland disease. I utilized machine learning to perform dimensionality reduction of high parameter flow cytometry data using a t-distributed stochastic neighbor embedding plugin to visualize the dynamic immune landscape of the lacrimal gland. I showed that IFNAR1 was ubiquitously expressed by many immune sets to varying degrees in the lacrimal glands. I showed that B lymphocytes enter the glands by 4 weeks of age and can express IFNAR1. While it was known that B cells are involved in the production of autoantibodies in later stages of disease, I demonstrated that there is a lymphocyte-intrinsic role for type I IFN signaling in the pathogenesis of lacrimal gland disease and through adoptive transfer studies determined that type I IFN signaling shapes B cell pathogenicity and phenotype. Taken together, these results broaden our understanding of the role of type I IFN signaling in lacrimal gland disease.
Details
- Title: Subtitle
- The role of type I interferon signaling in early dacryoadenitis in the nonobese diabetic mouse model of Sjögren’s disease
- Creators
- Merri-Grace Jones
- Contributors
- Scott M. Lieberman (Advisor)Stanley Perlman (Committee Member)Gail A. Bishop (Committee Member)Ali Jabbari (Committee Member)Kevin L. Legge (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Spring 2024
- DOI
- 10.25820/etd.007487
- Publisher
- University of Iowa
- Number of pages
- xv, 209 pages
- Copyright
- Copyright 2024 Merri-Grace Jones
- Language
- English
- Date submitted
- 04/18/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 172-209).
- Public Abstract (ETD)
Sjogren’s disease (SjD) is a chronic autoimmune disease of the lacrimal and salivary glands. Male nonobese diabetic (NOD) mice spontaneously develop lacrimal gland inflammation by 5-6 weeks of age. As disease progresses, B cells accumulate in the glands and produce antibodies resulting in glandular damage. Disruption of the type I interferon (IFN) signaling pathway protects NOD mice from developing lacrimal gland disease. While we previously showed that there is a lymphocyte-intrinsic role for type I IFN signaling in SjD, the impact of type I IFN signaling on B cell pathogenesis has not been defined. We identified B cell genes and pathways that are upregulated in early lacrimal autoimmunity. Adoptive transfer studies demonstrated that IFNAR1 expression on B cells exacerbates disease. Adoptive co-transfer studies of WT and IFNAR1-deficient cells revealed that intrinsic type I IFN signaling shapes B cell populations in the lacrimal glands and is required for the trafficking of autoreactive B cells to the glands. In vitro studies found that B cell phenotype can be shaped by IFN-α in a dose dependent manner. Together these data demonstrate that type I IFN signaling drives the development of lacrimal gland autoimmunity in NOD mice by shaping B cell phenotype and function.
- Academic Unit
- Interdisciplinary Studies Program
- Record Identifier
- 9984647454402771
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