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Göteborgs universitets publikationer

Giant cell arteritis. Epidemiological, morphological and molecular genetic studies

Författare och institution:
Vigdís Pétursdóttir (Institutionen för laboratoriemedicin , Avdelningen för patologi)
Antal sidor:
Datum för examination:
Patologens föreläsningssal, Sahlgrenska Universitetssjukhuset, Göteborg, kl 13.00
Sammanfattning (abstract):
Giant cell arteritis (GCA) is a chronic inflammatory disorder of unknown etiology, affecting large and medium-sized arteries, predominantly in postmenopausal women. Its pathogenesis is probably multifactorial. Several studies suggest that GCA is an antigen-driven disease. Symptoms such as fever and high sedimentation rate may indicate an infectious origin but so far GCA has not been shown to be a truly infectious vasculitis. Previous morphological studies suggest that calcification of the internal elastic membrane (IEM) might be a prerequisite for the disorder. Morphologically, the disease appears to start as a focal foreign-body giant cell reaction directed at the calcified IEM.The purpose of the present series of investigations was to analyse the annual and seasonal incidence of biopsy-verified GCA in Göteborg, to study giant cell aortitis morphologically and also to correlate the degree of inflammation with changes in cross-sectional dimensions in the temporal arteries. Further aims were to investigate the distribution and structure of estrogen receptor a (ER) in temporal artery tissue from GCA patients and controls.A total of 4971 temporal artery biopsies were investigated in Göteborg between 1976 and 1995. Of these 665 (13.4%) displayed signs of GCA which implies an average annual incidence rate of 22.2/ 100,000 inhabitants over 50 years of age. There was a statistically significant increase of 10.9% in the annual incidence during the period. Cyclic yearly fluctuations were not found. In contrast, the seasonal fluctuations were found to be statistically significant with peaks in autumn and late winter, which might indicate that exogenous factors are of importance for the pathogenesis. Staining for a-smooth muscle actin showed widespread areas totally devoid of immunoreactivity in the aortic media. Such areas were acellular and displayed granular calcifications. Focal granulomatous reaction with foreign-body giant cells was found at their ends. The present findings are analogous to the changes in temporal arteries in GCA and support that media atrophy and calcifications are prerequisites for the disorder and the target of the initial granulomatous reaction.Morphometrical analyses of different segments in the same artery revealed a significant positive correlation between the degree of inflammation and the media circumference as well as intima and media cross-sectional areas. While the media cross-sectional area was approximately 15% greater in the most inflamed segment compared with the least inflamed one, the intima area increased by 100%. Even in single cross sections, the intima area showed a positive correlation to the degree of inflammation. The results indicate that the inflammatory cells produce factors leading to local intimal thickening in GCA.The estrogen metabolism might influence the pathogenesis of GCA in several ways. Firstly, reduced estrogen influence might theoretically have negative effects on the vessel wall, thus causing media atrophy. Secondly, there is ample evidence that estrogen affects the immune system via ER in lymphocytes and macrophages. Immunocytochemical analysis displayed a positive cytoplasmic reaction in smooth muscle cells of the media in temporal arteries from patients with GCA and in non-GCA controls. Immunoreactivity was furthermore noticed in activated mononuclear inflammatory cells and giant cells in the GCA arteries. Western blot technique confirmed that the immunoreactive protein corresponds to the expected molecular weight of the ER. Nested RT-PCR and nucleotide sequence analysis of the ER-mRNAs revealed multiple transcript variants, the majority of which may be explained by alternative splicing. Somatic mutations were rare. No significant difference in the number of transcript variants was identified between GCA patients and controls. The combined Western blot and molecular genetic observations indicate that the observed cytoplasmic ER immunoreactivity in GCA and controls is related to an accumulation mainly of wild type ERa.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Medicinska grundvetenskaper ->
Cell- och molekylärbiologi ->
Giant cell arteritis, temporal artery, aorta, epidemiology, atrophy, calcification, estrogen receptor a, morphometry, immunocytochemistry, Western blot, molecular genetics
Ytterligare information:
Postens nummer:
Posten skapad:
2011-01-27 13:17

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