Interferon signaling in lupus-prone mice and systemic lupus erythematous
Abstract/Contents
- Abstract
- The majority of SLE patients are symptomatically treated using glucocorticoids, NSAIDs or cytotoxic agents. In the last decade, the field has seen a large push for pathophysiologically founded therapeutics, which are currently in late-stage clinical trails. Included in this category, is multiple therapeutics targeting IFNα1 (a Type I interferon, IFN-1), a known key player in SLE. In fact, a robust approach to subset patients is by the presence or absence of an IFNα Bio-signature, increased expression of transcripts regulated by IFNα, which correlates with disease severity. Additional studies in patients and murine models have supported a pathogenic role of Fin (Type II interferon, IFN-II). Nonetheless the mechanism by which IFN-I and IFN-II perturb the immune system in SLE remains unclear, and studies have revealed conflicting roles in murine models. Here, we seek to understand how IFN signaling modulates disease through cellular and molecular mechanisms in both mouse models of SLE and patients. First, we discover the role of individual IFN signaling components in MRL/lpr mice. Second, we identify single cell differences in cellular phenotype, cytokine signaling and immune function between IFN-high (IFN-H) and IFN-low (IFN-L) patients. To dissect the individual contributions of Type Type II IFNs and I in lupus disease a spontaneous murine model of SLE. We show increased IL-17-producing CD4+ T cells in the spleens and kidneys of STAT1-/- mice via shunted phosphorylation of STAT3/4. A similarly contrasting relationship is seen in the autoantibody produce- tin from these mice where STAT1-/- mice exhibit decreased autoantibody reactivity to SLE-associated antigens, whereas IRF9-/- mice exhibit increased autoantibody re- activity limited to histones. These data strongly suggest that IFN-I/II signaling proteins play differing roles in T helper cell polarization, B cell autoantibody production and interstitial kidney disease. In human work, we identify single cell differences in cellular phenotype, cytokine signaling and immune function between IFN-H and IFN-L patients. First, we determined the IFN signatures for 80 patients in the Stanford Registry SLE cohort. Autoantibody production of these patients was profiled using multiplexed protein arrays and confirmed higher autoantibody production in IFN-H patients as compared to IFN-L. Lastly, we used cytometry by time-of-flight (CyTOF), to perform simultaneous and unprecedented single-cell proteomic analysis of surface markers and intracellular functional proteins in SLE patients. We find that IFN-H and SLE patients in general exhibit decreased global STAT phosphorylation at baseline. However, increasing IFN score was associated with increased stat levels downstream of IFNα, IFNγ and IL-21 in addition to relevant clinical criteria.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Yiu, Gloria |
|---|---|
| Associated with | Stanford University, Program in Immunology. |
| Primary advisor | Utz, Paul |
| Thesis advisor | Utz, Paul |
| Thesis advisor | Negrin, Robert S |
| Thesis advisor | Nolan, Garry P |
| Thesis advisor | Robinson, William (William Hewitt) |
| Advisor | Negrin, Robert S |
| Advisor | Nolan, Garry P |
| Advisor | Robinson, William (William Hewitt) |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Gloria Yiu. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Gloria Yiu
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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