Year: 2018
Type: dissertation
Abstract: Little is known about the mechanisms underlying the clinical overlap of ankylosing spondylitis (AS) and inflammatory bowel disease (IBD). There is also a lack of reliable serological biomarkers to guide AS management. AS is a complex, male-dominant disease with HLA-B27 being the strongest genetic association. The ank/ank mouse is a murine model with serological and pathological features similar to human AS. Lipocalin 2 (murine Lcn2/human LCN2) is a secreted anti-microbial glycoprotein produced in multiple tissues including joint and gut. Given the functions of lipocalin 2 in infection, inflammation and bone remodeling, our aim is to assess whether lipocalin 2 is a key mediator of the gut-joint axis in AS and whether it would serve a better marker for treatment outcomes. The association of LCN2 with HLA-B27 and sex in patients is also analyzed. Chapter 2 shows that aberrant levels of Lcn2 are associated with ankylosis and gut pathology in ank/ank mice, indicating a potential mechanism underlying the overlap of AS and IBD. The interplay of gut inflammation and ankylosis in contributing to elevated Lcn2 levels suggests that the ank/ank mouse is a relevant animal model for the gut-joint interactions, as seen in AS. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a role in aberrant Lcn2 pathway in this AS model. Chapter 3 confirms the elevation of serum LCN2 in AS patients. Levels of LCN2 are associated with coexisting IBD and with the degree of ankylosis. The relationship of HLA-B27 positivity and sex with LCN2 implicates a host-microbe interaction underlying the gut-joint axis in AS. Chapter 4 demonstrates that normalization of LCN2 could be viewed as a treatment target in AS. Serum LCN2 served a more sensitive biomarker for treatment outcome in 89% of AS patients. HLA-B27 status and sex does affect LCN2 as a readout for assessing treatment outcome. The discovery of aberrant Lcn2/LCN2 reveals a relevant mechanism underlying the gut-joint axis in AS. The effect of PPARγ on aberrant Lcn2 pathway sheds lights on novel therapeutic targets for the disease. More knowledge of the dysregulation of Lcn2/LCN2 pathways will contribute to better AS management and more effective treatment strategies.
Source: TSpace (University of Toronto)
Author: Aifeng Lin
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2911984370