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Title: Polymorphonuclear leucocyte function in pregnancy
Author: Crocker, Ian Paul
ISNI:       0000 0001 3396 8649
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2000
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Clinical observations for more than a century have recognised an improvement in rheumatoid arthritis (RA) during pregnancy. This reduction in inflammation, coupled with an increase in intracellular infections, would strongly suggest a role for functionally altered polymorphonuclear leucocytes (PMN). This study has characterised the ex vivo behaviour of PMN throughout pregnancy and has compared these results with suitable age matched controls. Markers of PMN responsiveness and activation have been carefully chosen to give a thorough examination of cellular activity. An investigation of pregnant women in the third trimester has demonstrated a significant reduction in PMN intracellular killing. In association with this response, respiratory burst activity was reduced for PMN activated with physiological and non-physiological stimuli. There were no differences in the plasma levels of secondary granule lactoferrin, or in the stimulated expression and release of adhesion molecules, CD 11b, CD 18, or L-selectin. These results, plus the baseline values of adhesion molecules and receptor numbers/affinities, would suggest that in vivo activation or priming of PMN in pregnancy is not occurring. A longitudinal study of healthy women and RA sufferers has established a time course for these pregnancy changes. PMN respiratory burst activity progressively declined in both RA pregnant and healthy pregnant women from the middle of the second trimester. Responses returned to normal within 8 weeks of delivery and unstimulated levels remained unchanged throughout gestation. For PMN, certain morphological differences were highlight in RA. Low dose steroid treatment had no effect upon any of the PMN parameters measured. The importance of cytokines is becoming increasingly recognized in the process of inflammation. To test the significance of priming in pregnancy, PMN respiratory burst activity was measured following incubations with TNF-α, IL-8 , IL-1β, GM-CSF and G-CSF. From this set of experiments only prim ing by TNFα, IL-8 and GM-CSF showed a significant reduction in pregnant donors. Of the five cytokines considered, these three possess a single common, intracellular signaling pathway. This pathway involves the biologically important enzyme, Phospholipase A₂ (PLA₂). An investigation into circulating factors with a potential for PMN modulation has eliminated many of the common agents associated with pregnancy. One glycoprotein with possible in vivo potential was gravidin, a recently discovered PLA₂ inhibitor. Gravidin has been identified as the free secretory component (FSC) of IgA. This study has shown that circulatmg FSC is elevated in late pregnancy and that isolated FSC elicits a dose dependent reduction in stimulated PLA; activity and respiratory burst responses. Although gravidin may have an immunoregulatory role, PMN in pregnancy demonstrated reduced PLA₂ activity, regardless of gravidin. The NADPH oxidase system responsible for the respiratory burst has a direct requirement for polyunsaturated fatty acids, particular arachidonic acid (AA). All major fatty acids, including polyunsaturated fatty acids, were altered in the pregnant state. Of these differences in PMN, oleic and linolenic acid showed a significant increase, while stearic and importantly AA showed a significant reduction. A strong relationship appears to exist between serum fatty acids and cellular fatty acid content. In these investigations individual fatty acids and serum crossover incubations were shown to alter cellular fatty acid profiles and modify the PMN respiratory burst accordingly. To help strengthen this relationship, fatty acids and PMN behaviour were also recorded in patients with extrahepatic cholestatic jaundice. This condition, although unrelated to pregnaney, exerts similar effects upon RA. PMN in obstructive jaundice showed a significant reduction in their propensity for PLA₂ activity and respiratory burst responses. Again like pregnancy, polyunsaturated fatty acids in jaundice were significantly diminished and AA levels were markedly reduced. In conclusion, the findings of this study would imply that attenuations in PMN function offer a possible explanation for the remission of RA during pregnancy. This study has fostered the idea that pregnancy induced changes in circulating fatty acids may have a direct bearing on PMN fatty acids and their inflammatory responsiveness. The similarities in cells and fatty acids between jaundice and pregnancy, may explain the long established clinical benefits of these conditions upon inflammatory arthritis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Rheumatoid arthritis