Pathogenesis of cardiovascular disease in the presence and absence of rheumatoid arthritis

Curran, Samuel Arion (2012) Pathogenesis of cardiovascular disease in the presence and absence of rheumatoid arthritis. PhD thesis, University of Glasgow.

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Rheumatoid arthritis (RA) is a chronic inflammatory disease that although primarily affecting the joints is recognised as a systemic disease with a variety of co-morbidities. One such co-morbidity is cardiovascular disease (CVD) and patients with RA are at a two-fold increased risk of developing CVD compared to the general population. Indeed, CVD, principally as a result of atherosclerosis, is recognised as the leading cause of death in RA patients. In this study the vascular adventitia and serum samples from patients with co-existing RA and CVD were investigated to identify factors that could explain the increased CVD morbidity observed in RA patients. This involved culture-independent identification of bacterial signatures and histological evaluation for pro-inflammatory molecules and potential RA-associated autoantigens in the aortic adventitia. Additionally, serum samples from healthy controls, patients with RA or CVD alone, and patients with co-existing RA and CVD, were screened for a broad range of cytokines, chemokines and growth factors. These data provided the basis for further studies into the effect of cytokines on foam cell formation.
Histological evaluation of the aortic adventitia revealed that pronounced inflammatory infiltrates were detectable in all patients with CVD, regardless of rheumatic disease. To assess whether or not the inflammatory composition of the aortic adventitia differed between patients with or without RA, sections were examined using immunohistochemistry for a markers including TNFα, CD21 and heat shock proteins (HSP) 47 and 60, both of which have been implicated in the pathogenesis of RA and CVD. TNFα and HSP47 were confirmed in the aortic adventitia; however, neither CD21 nor HSP60 were detected. The expression of total TNFα was significantly elevated in RA+CVD compared to non-RA CVD patients. These data demonstrate that the aortic adventitia is a site of considerable immunological function and suggest a possible role for TNFα overexpression in the pathogenesis of CVD in RA.
Bacterial infection has been implicated as a causative agent for both RA and CVD. The present study used culture-independent methods to identify bacteria in the aortic adventitia of RA+CVD and non-RA CVD patients. The presence of bacterial DNA was confirmed in three of 11 RA+CVD and four of 11 non-RA CVD patients. The bacterial flora of RA+CVD patients was significantly less heterogeneous compared to non-RA CVD patients. Methylobacterium oryzae was detected in every RA+CVD patient positive for the presence of bacterial DNA. Subsequent in vitro characterisation demonstrated that M.oryzae stimulates mild Toll-like receptor 2 (TLR2), but not TLR4, signalling and, upon challenge of primary human macrophages, produces a robust pro-inflammatory response. Importantly, these findings implicate M. oryzae infection as playing a potential role in the pathogenesis of CVD in RA patients.
Previous studies have argued that the persistently high levels of systemic inflammation exhibited by RA patients are critical to elevated CVD risk. In the current study it was demonstrated that RA patients exhibit an altered systemic immune profile compared to non-RA CVD patients and healthy controls. The pro-inflammatory phenotype in co-morbind CVD and RA is suggestive of an environment that may promote atherosclerosis. Furthermore, RA+CVD patients were shown to possess an altered systemic immune phenotype compared to both RA and CVD patients. Notably, IL-1β, IL-2, IL-5, IL-8, IL-13, IL-17, Monokine induced by gamma interferon (MIG), Granulocyte colony-stimulating factor (G-CSF) and Granulocyte macrophage colony stimulating factor (GM-CSF) expression was greater in the serum of RA+CVD patients compared to the additive values of the RA and CVD patients.
The formation of lipid-rich foam cells is a major feature of atherosclerosis pathogenesis and is partially dependent on the inflammatory environment. The present study demonstrated that GM-CSF stimulation significantly decreased the rate at which human primary macrophages could endocytose oxLDL and form foam cells. The effect of dextran sulphate, a known competitive inhibitor of scavenger receptors, on the ability of GM-CSF stimulated macrophages to differentiate into foam cells revealed that GM-CSF decreases the concentration of dextran sulphate required to successfully inhibit scavenger receptor-mediated ox-LDL uptake; suggesting that GM-CSF-stimulated macrophages express less scavenger receptors on the cell surface. However, subsequent investigation demonstrated that GM-CSF stimulation did not decrease expression of the currently recognised scavenger receptors that are capable of oxLDL recognition (SR-A1, SR-B1, CD36 and MARCO). These data imply that the overexpression of GM-CSF observed in RA and RA+CVD patients may provide some atheroprotective benefit. This has clinical implications for future anti-RA drugs which target GM-CSF function.
In summary, the data presented in this thesis demonstrate that RA+CVD patients exhibit immunological and pathological alterations both in the aortic adventitia and systemically. Further research will, over time, provide insight into the mechanisms underlying increased CVD burden in RA.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School
Supervisor's Name: Riggio, Dr. Marcello and Goodyear, Dr. Carl
Date of Award: 2012
Depositing User: Mrs Marie Cairney
Unique ID: glathesis:2012-3849
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 Jan 2013 13:32
Last Modified: 16 Oct 2014 09:01

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