Abstract
ObjectiveGlucocorticoid (GC) sensitivity is highly variable among individuals and has been associated with susceptibility to develop (auto-)inflammatory disorders. The purpose of the study was to assess GC sensitivity in Behçet's disease (BD) by studying the distribution of four GC receptor (GR) gene polymorphisms and by measuring in vitro cellular GC sensitivity.MethodsHealthy controls and patients with BD in three independent cohorts were genotyped for four functional GR gene polymorphisms. To gain insight into functional differences in in vitro GC sensitivity, 19 patients with BD were studied using two bioassays and a whole-cell dexamethasone-binding assay. Finally, mRNA expression levels of GR splice variants (GR-α and GR-β) were measured.ResultsHealthy controls and BD patients in the three separate cohorts had similar distributions of the four GR polymorphisms. The Bcll and 9β minor alleles frequency differed significantly between Caucasians and Mideast and Turkish individuals.At the functional level, a decreased in vitro cellular GC sensitivity was observed. GR number in peripheral blood mononuclear cells was higher in BD compared with controls. The ratio of GR-α/GR-β mRNA expression levels was significantly lower in BD.ConclusionsPolymorphisms in the GR gene are not associated with susceptibility to BD. However, in vitro cellular GC sensitivity is decreased in BD, possibly mediated by a relative higher expression of the dominant negative GR-β splice variant. This decreased in vitro GC sensitivity might play an as yet unidentified role in the pathophysiology of BD.
Highlights
Behcet’s disease (BD) is an inflammatory disorder characterized by recurrent episodes of orogenital ulcers, uveitis, arthritis, and skin lesions
The results of our study suggest that decreased GC sensitivity might play a role in the pathophysiology of BD
Both transactivating and transrepressing pathways of GC action seem to be affected in BD, together with an altered expression of the GC receptor (GR) in peripheral blood mononuclear cells (PBMC)
Summary
Behcet’s disease (BD) is an inflammatory disorder characterized by recurrent episodes of orogenital ulcers, uveitis, arthritis, and skin lesions. Less frequent symptoms include gastrointestinal lesions and involvement of the central and peripheral nervous system. The onset of disease is typically in the third or fourth decade of life and affects men and women. BD is common along the ancient Silk Road, which extends from Eastern Asia to the Mediterranean area. The highest prevalence occurs in Turkey (80–420 cases per 100.000), followed by Middle and Far Eastern countries (13.5–20 cases per 100.000). The prevalence in Western countries is much lower; w0.12–5.1 per 100.000 [1, 2, 3]
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