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Title: The role of nitric oxide in lacrimal gland hypofunction and the antisecretory action of anti-muscarinic autoantibodies associated with Sjögren's syndrome
Author: Malone, John Charles
ISNI:       0000 0004 2733 8300
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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Sjogren's syndrome (SjS) is a systemic autoimmune disorder specifically targeting the exocrine glands, primarily the salivary and lacrimal glands. The autoimmune attack upon these organs is characterised by lymphocytic infiltration of the salivary and lacrimal glands, leading to an impairment of secretory function. Little is known about the mechanisms underlying glandular hypofunction, because the condition is very difficult to detect at an early stage, rendering treatment difficult. Recent studies in salivary glands have identified a mechanism whereby the inflammatory mediator NO, acting through cGMP and cADPr, can modulate the fluid secretory process. Thus NO production may contribute to the glandular hypofunction associated with SjS. The likelihood that NO plays a key role in the aetiologvof SjS would be greatly increased if it may be demonstrated that NO perturbed fluid secretion in lacrimal, as well as salivary gland acinar cells. Using microfluorimetric and patch clamp techniques I have shown that the acute response of lacrimal acinar cells exposed to NO is an amplification of the muscarinic agonist evoked Ca2+ signal. Also, that this amplification is probably mediated through increased ryanodine receptor sensitivity. Chronic exposure to NO in salivary gland acinar cells has been shown to inhibit the response to muscarinic agonist. Observation of the same effect in lacrimal gland cells would suggest that increased levels of NO may be a unifying factor between two separate secretory organs for the glandular hypofunction associated with SjS. Inhibition of secretion by anti-muscarinic receptor autoantibodies represents a complimentary mechanism of glandular hypofunction and one which also has the potential to aid in early detection of the condition. These autoantibodies are very difficult to detect using conventional immunological techniques, but represent an attractive target for being the basis of a diagnostic test. My data demonstrate a similar pattern of response in lacrimal to salivary gland acinar cells, but also demonstrate that lacrimal acinar cells are capable of endogenous NO production. The mechanism by which NO modulates secretory mechanisms appears to be a universal feature of the exocrine glands affected by SjS. However, my data suggest at least quantitative differences in the role of NO in glandular function. These data represent further elucidation of the role of NO in glandular hypofunction in SjS, highlighting fundamental differences between two similar gland systems affected by SjS, potentially affecting avenues of treatment. I have also demonstrated that anti-muscarinic receptor autoantibodies may be detected using conventional microfluorimetric techniques and I have developed a semi-automated fluorimetric tool that allows rapid screening and detection of autoantibodies within the isolated IgG fraction of patient serum. Preliminary data indicate that the sensitivity and specificity of detection of antimuscarinic autoantibodies was not sufficiently high enough to offer significant improvement over current methods for detecting SjS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available